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Chalkley MBL, Guerin LN, Iyer T, Mallahan S, Nelson S, Sahin M, Hodges E, Ess KC, Ihrie RA. Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome. Hum Mol Genet 2025; 34:684-698. [PMID: 39877967 PMCID: PMC11973902 DOI: 10.1093/hmg/ddae199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 11/15/2024] [Accepted: 01/22/2025] [Indexed: 01/31/2025] Open
Abstract
Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether phenotypes are also present in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
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Affiliation(s)
- Mary-Bronwen L Chalkley
- Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
| | - Lindsey N Guerin
- Department of Biochemistry, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
| | - Tenhir Iyer
- Department of Pediatrics, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, Tennessee, 37232, United States of America
| | - Samantha Mallahan
- Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
| | - Sydney Nelson
- Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
| | - Mustafa Sahin
- Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts, 02115, United States of America
| | - Emily Hodges
- Department of Biochemistry, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN, 37232, USA
| | - Kevin C Ess
- Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
- Department of Pediatrics, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, Tennessee, 37232, United States of America
- Department of Pediatrics - Neurology, University of Colorado Anschutz Medical Campus, 13123 E. 16th Ave., Aurora, Colorado, 80045, United States of America
| | - Rebecca A Ihrie
- Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, Tennessee, 37232, United States of America
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave, Nashville, TN, 37232, USA
- Department of Pediatrics - Neurology, University of Colorado Anschutz Medical Campus, 13123 E. 16th Ave., Aurora, Colorado, 80045, United States of America
- Department of Neurological Surgery, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, Tennessee, 37232, United States of America
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2
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Hoffmann J, Schütze TM, Kolodziejczyk A, Küster K, Kränkel A, Reinhardt S, Derihaci RP, Birdir C, Wimberger P, Koseki H, Albert M. Canonical and non-canonical PRC1 differentially contribute to regulation of neural stem cell fate. Life Sci Alliance 2025; 8:e202403006. [PMID: 39933923 PMCID: PMC11814486 DOI: 10.26508/lsa.202403006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Neocortex development is characterized by sequential phases of neural progenitor cell (NPC) expansion, neurogenesis, and gliogenesis. Polycomb-mediated epigenetic mechanisms are known to play important roles in regulating the lineage potential of NPCs during development. The composition of Polycomb repressive complex 1 (PRC1) is highly diverse in mammals and was hypothesized to contribute to context-specific regulation of cell fate. Here, we have performed a side-by-side comparison of the role of canonical PRC1.2/1.4 and non-canonical PRC1.3/1.5, all of which are expressed in the developing neocortex, in NSC proliferation and differentiation. We found that the deletion of Pcgf2/4 in NSCs led to a strong reduction in proliferation and to altered lineage fate, both during the neurogenic and gliogenic phase, whereas Pcgf3/5 played a minor role. Mechanistically, genes encoding stem cell and neurogenic factors were bound by PRC1 and differentially expressed upon Pcgf2/4 deletion. Thus, rather than different PRC1 subcomplexes contributing to different phases of neural development, we found that canonical PRC1 played a more significant role in NSC regulation during proliferative, neurogenic, and gliogenic phases compared with non-canonical PRC1.
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Affiliation(s)
- Janine Hoffmann
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Theresa M Schütze
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Annika Kolodziejczyk
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Karolin Küster
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Annekathrin Kränkel
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, Technology Platform of the TUD Dresden University of Technology, Dresden, Germany
| | - Susanne Reinhardt
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, Technology Platform of the TUD Dresden University of Technology, Dresden, Germany
| | - Razvan P Derihaci
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases, Dresden, Germany
| | - Cahit Birdir
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- Center for Feto/Neonatal Health, Technische Universität Dresden, Dresden, Germany
| | - Pauline Wimberger
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases, Dresden, Germany
| | - Haruhiko Koseki
- Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mareike Albert
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
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Yao TF, Wang ZY, Sun L, Yu SX, Yu HD, Yang ZZ, Li WZ, Niu L, Sun D, Shi YH, Li JQ, Liu WQ, Liu XZ, Zuo ZF. DNMT3b-mediated CpA methylation facilitates REST binding and gene silencing and exacerbates hippocampal demyelination in diabetic mice. J Biol Chem 2025; 301:108137. [PMID: 39730060 PMCID: PMC11910331 DOI: 10.1016/j.jbc.2024.108137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024] Open
Abstract
The remyelination process within the diabetes mellitus (DM) brain is inhibited, and dynamic interactions between DNA methylation and transcription factors are critical for this process. Repressor element-1 silencing transcription factor (REST) is a major regulator of oligodendrocyte differentiation, and the role of REST on DM remyelination remains to be investigated. Here, we investigated the effects of REST and DNA methylation on DM remyelination and explored the underlying mechanisms. In this study, using a diabetic mouse model, we found that myelin damage preceded neuronal damage and caused cognitive impairment in DM mice. Inhibition of REST by X5050 and DNMT3b by Naomycin A promoted myelin regeneration in the hippocampus and ameliorated cognitive deficits in DM mice. In addition, CpA methylation of the RE-1 locus of the CNTN1 gene was able to increase the binding capacity of REST. We also observed that CNTN1 promotes oligodendrocyte maturation, facilitates the ratio of microglia to pro-regenerative phenotypes as well as enhances the ability of microglia to remove myelin debris. Our findings suggest that REST and DNMT3b expression inhibit CNTN1 expression and exacerbate myelin damage. This mechanism of gene silencing may be associated with DNMT3b-mediated CpA methylation of the REST binding site in the promoter region of the CNTN1 gene. We also identified the role for CNTN1 in promoting oligodendrocyte precursor cell maturation and myelin debris removal during remyelination.
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Affiliation(s)
- Tie-Feng Yao
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Zhi-Yun Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Lu Sun
- Department of Pathology, Jinzhou Medical University, Jinzhou, China
| | - Sheng-Xue Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Hong-Dan Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Zheng-Zhong Yang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wan-Ze Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Lin Niu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Die Sun
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Ya-Hui Shi
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Jun-Qi Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wen-Qiang Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Xue-Zheng Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
| | - Zhong-Fu Zuo
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
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4
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Kodila ZN, Shultz SR, Yamakawa GR, Mychasiuk R. Critical Windows: Exploring the Association Between Perinatal Trauma, Epigenetics, and Chronic Pain. Neuroscientist 2024; 30:574-596. [PMID: 37212380 PMCID: PMC11439237 DOI: 10.1177/10738584231176233] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Chronic pain is highly prevalent and burdensome, affecting millions of people worldwide. Although it emerges at any point in life, it often manifests in adolescence. Given that adolescence is a unique developmental period, additional strains associated with persistent and often idiopathic pain lead to significant long-term consequences. While there is no singular cause for the chronification of pain, epigenetic modifications that lead to neural reorganization may underpin central sensitization and subsequent manifestation of pain hypersensitivity. Epigenetic processes are particularly active during the prenatal and early postnatal years. We demonstrate how exposure to various traumas, such as intimate partner violence while in utero or adverse childhood experiences, can significantly influence epigenetic regulation within the brain and in turn modify pain-related processes. We provide compelling evidence that the burden of chronic pain is likely initiated early in life, often being transmitted from mother to offspring. We also highlight two promising prophylactic strategies, oxytocin administration and probiotic use, that have the potential to attenuate the epigenetic consequences of early adversity. Overall, we advance understanding of the causal relationship between trauma and adolescent chronic pain by highlighting epigenetic mechanisms that underlie this transmission of risk, ultimately informing how to prevent this rising epidemic.
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Affiliation(s)
- Zoe N. Kodila
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Sandy R. Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
- Health Sciences, Vancouver Island University, Nanaimo, Canada
| | - Glenn R. Yamakawa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia
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5
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Ma S, Wang L, Zhang J, Geng L, Yang J. The role of transcriptional and epigenetic modifications in astrogliogenesis. PeerJ 2024; 12:e18151. [PMID: 39314847 PMCID: PMC11418818 DOI: 10.7717/peerj.18151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/31/2024] [Indexed: 09/25/2024] Open
Abstract
Astrocytes are widely distributed and play a critical role in the central nervous system (CNS) of the human brain. During the development of CNS, astrocytes provide essential nutritional and supportive functions for neural cells and are involved in their metabolism and pathological processes. Despite the numerous studies that have reported on the regulation of astrogliogenesis at the transcriptional and epigenetic levels, there is a paucity of literature that provides a comprehensive summary of the key factors influencing this process. In this review, we analyzed the impact of transcription factors (e.g., NFI, JAK/STAT, BMP, and Ngn2), DNA methylation, histone acetylation, and noncoding RNA on astrocyte behavior and the regulation of astrogliogenesis, hope it enhances our comprehension of the mechanisms underlying astrogliogenesis and offers a theoretical foundation for the treatment of patients with neurological diseases.
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Affiliation(s)
- Shuangping Ma
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Lei Wang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Junhe Zhang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
| | - Lujing Geng
- College of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China
| | - Junzheng Yang
- Institutes of Health Central Plains, Tissue Engineering and Regenerative Clinical Medicine Center, Xinxiang Medical University, Xinxiang, China
- Guangdong Nephrotic Drug Engineering Technology Research Center, The R&D Center of Drug for Renal Diseases, Consun Pharmaceutical Group, Guangzhou, China
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6
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Thapak P, Gomez-Pinilla F. The bioenergetics of traumatic brain injury and its long-term impact for brain plasticity and function. Pharmacol Res 2024; 208:107389. [PMID: 39243913 DOI: 10.1016/j.phrs.2024.107389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/19/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.
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Affiliation(s)
- Pavan Thapak
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA
| | - Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, CA 90095, USA.
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7
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Vivi E, Di Benedetto B. Brain stars take the lead during critical periods of early postnatal brain development: relevance of astrocytes in health and mental disorders. Mol Psychiatry 2024; 29:2821-2833. [PMID: 38553540 PMCID: PMC11420093 DOI: 10.1038/s41380-024-02534-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 09/25/2024]
Abstract
In the brain, astrocytes regulate shape and functions of the synaptic and vascular compartments through a variety of released factors and membrane-bound proteins. An imbalanced astrocyte activity can therefore have drastic negative impacts on brain development, leading to the onset of severe pathologies. Clinical and pre-clinical studies show alterations in astrocyte cell number, morphology, molecular makeup and astrocyte-dependent processes in different affected brain regions in neurodevelopmental (ND) and neuropsychiatric (NP) disorders. Astrocytes proliferate, differentiate and mature during the critical period of early postnatal brain development, a time window of elevated glia-dependent regulation of a proper balance between synapse formation/elimination, which is pivotal in refining synaptic connectivity. Therefore, any intrinsic and/or extrinsic factors altering these processes during the critical period may result in an aberrant synaptic remodeling and onset of mental disorders. The peculiar bridging position of astrocytes between synaptic and vascular compartments further allows them to "compute" the brain state and consequently secrete factors in the bloodstream, which may serve as diagnostic biomarkers of distinct healthy or disease conditions. Here, we collect recent advancements regarding astrogenesis and astrocyte-mediated regulation of neuronal network remodeling during early postnatal critical periods of brain development, focusing on synapse elimination. We then propose alternative hypotheses for an involvement of aberrancies in these processes in the onset of ND and NP disorders. In light of the well-known differential prevalence of certain brain disorders between males and females, we also discuss putative sex-dependent influences on these neurodevelopmental events. From a translational perspective, understanding age- and sex-dependent astrocyte-specific molecular and functional changes may help to identify biomarkers of distinct cellular (dys)functions in health and disease, favouring the development of diagnostic tools or the selection of tailored treatment options for male/female patients.
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Affiliation(s)
- Eugenia Vivi
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany
| | - Barbara Di Benedetto
- Laboratory of Neuro-Glia Pharmacology, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053, Regensburg, Germany.
- Regensburg Center of Neuroscience, University of Regensburg, Regensburg, Germany.
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MacArthur IC, Ma L, Huang CY, Bhavsar H, Suzuki M, Dawlaty MM. Developmental DNA demethylation is a determinant of neural stem cell identity and gliogenic competence. SCIENCE ADVANCES 2024; 10:eado5424. [PMID: 39196941 PMCID: PMC11352921 DOI: 10.1126/sciadv.ado5424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/24/2024] [Indexed: 08/30/2024]
Abstract
DNA methylation is extensively reconfigured during development, but the functional significance and cell type-specific dependencies of DNA demethylation in lineage specification remain poorly understood. Here, we demonstrate that developmental DNA demethylation, driven by ten-eleven translocation 1/2/3 (TET1/2/3) enzymes, is essential for establishment of neural stem cell (NSC) identity and gliogenic potential. We find that loss of all three TETs during NSC specification is dispensable for neural induction and neuronal differentiation but critical for astrocyte and oligodendrocyte formation, demonstrating a selective loss of glial competence. Mechanistically, TET-mediated demethylation was essential for commissioning neural-specific enhancers in proximity to master neurodevelopmental and glial transcription factor genes and for induction of these genes. Consistently, loss of all three TETs in embryonic NSCs in mice compromised glial gene expression and corticogenesis. Thus, TET-dependent developmental demethylation is an essential regulatory mechanism for neural enhancer commissioning during NSC specification and is a cell-intrinsic determinant of NSC identity and gliogenic potential.
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Affiliation(s)
- Ian C. MacArthur
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA
- Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - Liyang Ma
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA
- Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - Cheng-Yen Huang
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA
- Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - Hrutvik Bhavsar
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA
- Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
| | - Masako Suzuki
- Department of Nutrition, Texas A&M University, 2253 TAMU, Carter Mattil 214A, College Station, TX 77840, USA
| | - Meelad M. Dawlaty
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 1046142, USA
- Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave, Bronx, NY 10461, USA
- Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA
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9
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Gomez-Pinilla F, Thapak P. Exercise epigenetics is fueled by cell bioenergetics: Supporting role on brain plasticity and cognition. Free Radic Biol Med 2024; 220:43-55. [PMID: 38677488 PMCID: PMC11144461 DOI: 10.1016/j.freeradbiomed.2024.04.237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/04/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.
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Affiliation(s)
- Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Pavan Thapak
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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10
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Chalkley MBL, Guerin LN, Iyer T, Mallahan S, Nelson S, Sahin M, Hodges E, Ess KC, Ihrie RA. Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.04.597443. [PMID: 38895266 PMCID: PMC11185654 DOI: 10.1101/2024.06.04.597443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether such phenotypes are also seen in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
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Affiliation(s)
- Mary-Bronwen L. Chalkley
- Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Lindsey N. Guerin
- Department of Biochemistry, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Tenhir Iyer
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Samantha Mallahan
- Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Sydney Nelson
- Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Mustafa Sahin
- Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Emily Hodges
- Department of Biochemistry, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Kevin C. Ess
- Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, Colorado, United States of America
| | - Rebecca A. Ihrie
- Department of Cell & Developmental Biology, School of Medicine Basic Sciences, Vanderbilt University, Nashville, Tennessee, United States of America
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
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11
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Kunoh S, Nakashima H, Nakashima K. Epigenetic Regulation of Neural Stem Cells in Developmental and Adult Stages. EPIGENOMES 2024; 8:22. [PMID: 38920623 PMCID: PMC11203245 DOI: 10.3390/epigenomes8020022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/18/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.
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Affiliation(s)
| | - Hideyuki Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
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12
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Lossi L, Castagna C, Merighi A. An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions. Int J Mol Sci 2024; 25:3881. [PMID: 38612690 PMCID: PMC11011998 DOI: 10.3390/ijms25073881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer's or Parkinson's disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.
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Affiliation(s)
| | | | - Adalberto Merighi
- Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 10095 Grugliasco, Italy; (L.L.); (C.C.)
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13
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Frith TJR, Briscoe J, Boezio GLM. From signalling to form: the coordination of neural tube patterning. Curr Top Dev Biol 2023; 159:168-231. [PMID: 38729676 DOI: 10.1016/bs.ctdb.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
The development of the vertebrate spinal cord involves the formation of the neural tube and the generation of multiple distinct cell types. The process starts during gastrulation, combining axial elongation with specification of neural cells and the formation of the neuroepithelium. Tissue movements produce the neural tube which is then exposed to signals that provide patterning information to neural progenitors. The intracellular response to these signals, via a gene regulatory network, governs the spatial and temporal differentiation of progenitors into specific cell types, facilitating the assembly of functional neuronal circuits. The interplay between the gene regulatory network, cell movement, and tissue mechanics generates the conserved neural tube pattern observed across species. In this review we offer an overview of the molecular and cellular processes governing the formation and patterning of the neural tube, highlighting how the remarkable complexity and precision of vertebrate nervous system arises. We argue that a multidisciplinary and multiscale understanding of the neural tube development, paired with the study of species-specific strategies, will be crucial to tackle the open questions.
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Affiliation(s)
| | - James Briscoe
- The Francis Crick Institute, London, United Kingdom.
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14
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Luo X, Xu M, Guo W. Adult neurogenesis research in China. Dev Growth Differ 2023; 65:534-545. [PMID: 37899611 DOI: 10.1111/dgd.12900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/22/2023] [Accepted: 10/25/2023] [Indexed: 10/31/2023]
Abstract
Neural stem cells are multipotent stem cells that generate functional newborn neurons through a process called neurogenesis. Neurogenesis in the adult brain is tightly regulated and plays a pivotal role in the maintenance of brain function. Disruption of adult neurogenesis impairs cognitive function and is correlated with numerous neurologic disorders. Deciphering the mechanisms underlying adult neurogenesis not only advances our understanding of how the brain functions, but also offers new insight into neurologic diseases and potentially contributes to the development of effective treatments. The field of adult neurogenesis is experiencing significant growth in China. Chinese researchers have demonstrated a multitude of factors governing adult neurogenesis and revealed the underlying mechanisms of and correlations between adult neurogenesis and neurologic disorders. Here, we provide an overview of recent advancements in the field of adult neurogenesis due to Chinese scientists.
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Affiliation(s)
- Xing Luo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- Graduate School, University of Chinese Academy of Sciences, Beijing, China
| | - Mingyue Xu
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- Graduate School, University of Chinese Academy of Sciences, Beijing, China
| | - Weixiang Guo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
- Graduate School, University of Chinese Academy of Sciences, Beijing, China
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15
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Wang J, Xu L, Peng D, Zhu Y, Gu Z, Yao Y, Li H, Cao X, Fu CY, Zheng M, Song X, Ding Y, Shen Y, Zhong J, Chen YY, Hu J, Wang LL. IFN-γ-STAT1-mediated CD8 + T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury. Inflamm Regen 2023; 43:12. [PMID: 36782279 PMCID: PMC9926765 DOI: 10.1186/s41232-023-00263-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/31/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Spinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs. METHODS The infiltration, state, and location of CD8+ T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8+ T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin+ NSCs after SCI in vivo. RESULTS A prolonged increase of activated CD8+ T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin+ NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8+ T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes. CONCLUSION In conclusion, CD8+ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8+ T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.
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Affiliation(s)
- Jingyu Wang
- grid.412465.0Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009 China
| | - Lintao Xu
- grid.412465.0Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009 China
| | - Deqing Peng
- grid.417401.70000 0004 1798 6507Department of Neurosurgery, Center for Rehabilitation Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital Hangzhou Medical College), Hangzhou, Zhejiang China
| | - Yongjian Zhu
- grid.412465.0Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009 China
| | - Zhaowen Gu
- grid.412465.0Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310009 China
| | - Ying Yao
- grid.412465.0Department of Neurointensive Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009 China
| | - Heyangzi Li
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Xi Cao
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Chun-yan Fu
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Mingzhi Zheng
- grid.506977.a0000 0004 1757 7957School of Basic Medical Sciences & Forensic Medicine of Hangzhou Medical College, Hangzhou, 310053 China
| | - Xinghui Song
- grid.13402.340000 0004 1759 700XCentral Laboratory, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006 China
| | - Yueming Ding
- grid.13402.340000 0004 1759 700XSchool of Medicine, Zhejiang University City College, Hangzhou, 310015 China
| | - Yueliang Shen
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Jinjie Zhong
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences and Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Ying-ying Chen
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences and Department of Obstetrics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 China
| | - Jue Hu
- School of Basic Medical Sciences & Forensic Medicine of Hangzhou Medical College, Hangzhou, 310053, China.
| | - Lin-lin Wang
- grid.13402.340000 0004 1759 700XDepartment of Basic Medicine Sciences and Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058 China
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16
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Selcen I, Prentice E, Casaccia P. The epigenetic landscape of oligodendrocyte lineage cells. Ann N Y Acad Sci 2023; 1522:24-41. [PMID: 36740586 PMCID: PMC10085863 DOI: 10.1111/nyas.14959] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The epigenetic landscape of oligodendrocyte lineage cells refers to the cell-specific modifications of DNA, chromatin, and RNA that define a unique gene expression pattern of functionally specialized cells. Here, we focus on the epigenetic changes occurring as progenitors differentiate into myelin-forming cells and respond to the local environment. First, modifications of DNA, RNA, nucleosomal histones, key principles of chromatin organization, topologically associating domains, and local remodeling will be reviewed. Then, the relationship between epigenetic modulators and RNA processing will be explored. Finally, the reciprocal relationship between the epigenome as a determinant of the mechanical properties of cell nuclei and the target of mechanotransduction will be discussed. The overall goal is to provide an interpretative key on how epigenetic changes may account for the heterogeneity of the transcriptional profiles identified in this lineage.
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Affiliation(s)
- Ipek Selcen
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York, USA.,Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA
| | - Emily Prentice
- Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA.,Graduate Program in Biology, The Graduate Center of The City University of New York, New York, New York, USA
| | - Patrizia Casaccia
- Graduate Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York, USA.,Neuroscience Initiative, Advanced Science Research Center, The Graduate Center of The City University of New York, New York, New York, USA.,Graduate Program in Biology, The Graduate Center of The City University of New York, New York, New York, USA
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17
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Xie J, Xie L, Wei H, Li XJ, Lin L. Dynamic Regulation of DNA Methylation and Brain Functions. BIOLOGY 2023; 12:152. [PMID: 36829430 PMCID: PMC9952911 DOI: 10.3390/biology12020152] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
DNA cytosine methylation is a principal epigenetic mechanism underlying transcription during development and aging. Growing evidence suggests that DNA methylation plays a critical role in brain function, including neurogenesis, neuronal differentiation, synaptogenesis, learning, and memory. However, the mechanisms underlying aberrant DNA methylation in neurodegenerative diseases remain unclear. In this review, we provide an overview of the contribution of 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) to brain development and aging, with a focus on the roles of dynamic 5mC and 5hmC changes in the pathogenesis of neurodegenerative diseases, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Identification of aberrant DNA methylation sites could provide potential candidates for epigenetic-based diagnostic and therapeutic strategies for neurodegenerative diseases.
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Affiliation(s)
| | | | | | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
| | - Li Lin
- Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
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18
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Hernaiz A, Sentre S, Betancor M, López-Pérez Ó, Salinas-Pena M, Zaragoza P, Badiola JJ, Toivonen JM, Bolea R, Martín-Burriel I. 5-Methylcytosine and 5-Hydroxymethylcytosine in Scrapie-Infected Sheep and Mouse Brain Tissues. Int J Mol Sci 2023; 24:ijms24021621. [PMID: 36675131 PMCID: PMC9864596 DOI: 10.3390/ijms24021621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Scrapie is a neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies or prion diseases, which are caused by an infectious isoform of the innocuous cellular prion protein (PrPC) known as PrPSc. DNA methylation, one of the most studied epigenetic mechanisms, is essential for the proper functioning of the central nervous system. Recent findings point to possible involvement of DNA methylation in the pathogenesis of prion diseases, but there is still a lack of knowledge about the behavior of this epigenetic mechanism in such neurodegenerative disorders. Here, we evaluated by immunohistochemistry the 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels in sheep and mouse brain tissues infected with scrapie. Expression analysis of different gene coding for epigenetic regulatory enzymes (DNMT1, DNMT3A, DNMT3B, HDAC1, HDAC2, TET1, and TET2) was also carried out. A decrease in 5mC levels was observed in scrapie-affected sheep and mice compared to healthy animals, whereas 5hmC displayed opposite patterns between the two models, demonstrating a decrease in 5hmC in scrapie-infected sheep and an increase in preclinical mice. 5mC correlated with prion-related lesions in mice and sheep, but 5hmC was associated with prion lesions only in sheep. Differences in the expression changes of epigenetic regulatory genes were found between both disease models, being differentially expressed Dnmt3b, Hdac1, and Tet1 in mice and HDAC2 in sheep. Our results support the evidence that DNA methylation in both forms, 5mC and 5hmC, and its associated epigenetic enzymes, take part in the neurodegenerative course of prion diseases.
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Affiliation(s)
- Adelaida Hernaiz
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Sara Sentre
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Marina Betancor
- Centro de Encefalopatías y Enfermedades Transmisibles Emergentes (CEETE), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Óscar López-Pérez
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Mónica Salinas-Pena
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Pilar Zaragoza
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, 28029 Madrid, Spain
| | - Juan José Badiola
- Centro de Encefalopatías y Enfermedades Transmisibles Emergentes (CEETE), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Janne Markus Toivonen
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, 28029 Madrid, Spain
| | - Rosa Bolea
- Centro de Encefalopatías y Enfermedades Transmisibles Emergentes (CEETE), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
| | - Inmaculada Martín-Burriel
- Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
- Centro de Encefalopatías y Enfermedades Transmisibles Emergentes (CEETE), Facultad de Veterinaria, Universidad de Zaragoza, IA2, IIS Aragón, 50013 Zaragoza, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-976-761662
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19
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Shen XY, Shi SH, Li H, Wang CC, Zhang Y, Yu H, Li YB, Liu B. The role of Gadd45b in neurologic and neuropsychiatric disorders: An overview. Front Mol Neurosci 2022; 15:1021207. [PMID: 36311022 PMCID: PMC9606402 DOI: 10.3389/fnmol.2022.1021207] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/21/2022] [Indexed: 11/26/2022] Open
Abstract
Growth arrest and DNA damage-inducible beta (Gadd45b) is directly intertwined with stress-induced DNA repair, cell cycle arrest, survival, and apoptosis. Previous research on Gadd45b has focused chiefly on non-neuronal cells. Gadd45b is extensively expressed in the nervous system and plays a critical role in epigenetic DNA demethylation, neuroplasticity, and neuroprotection, according to accumulating evidence. This article provided an overview of the preclinical and clinical effects of Gadd45b, as well as its hypothesized mechanisms of action, focusing on major psychosis, depression, autism, stroke, seizure, dementia, Parkinson’s disease, and autoimmune diseases of the nervous system.
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Affiliation(s)
- Xiao-yue Shen
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shu-han Shi
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Heng Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Cong-cong Wang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yao Zhang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Hui Yu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yan-bin Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
- Yan-bin Li,
| | - Bin Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
- *Correspondence: Bin Liu,
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20
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Guan Z, Liang Y, Wang X, Zhu Z, Yang A, Li S, Yu J, Niu B, Wang J. Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis. Neurochem Res 2022; 47:3709-3722. [PMID: 35960485 DOI: 10.1007/s11064-022-03717-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/23/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022]
Abstract
Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein-protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant.
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Affiliation(s)
- Zhen Guan
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Yingchao Liang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Xiuwei Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Zhiqiang Zhu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Aiyun Yang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Shen Li
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Jialu Yu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Bo Niu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Jianhua Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Translational Medicine Laboratory, Capital Institute of Pediatrics, Beijing, 100020, China.
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21
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Savchenko VL. Modulation of Excitatory Synaptic Transmission During Cannabinoid Receptor Activation. Cell Mol Neurobiol 2022; 42:1933-1947. [PMID: 33723716 PMCID: PMC11421691 DOI: 10.1007/s10571-021-01074-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 03/01/2021] [Indexed: 10/21/2022]
Abstract
The present research has reported that cannabinoid receptor 1 (CB1) agonist, delta-(9)-tetrahydrocannabinol (THC) modulates synaptogenesis during overexcitation. Microtubule and synaptic distribution, poly(ADP)-ribose (PAR) accumulation were estimated during overexcitation and in the presence of THC. Low concentration of THC (10 nM) increased synaptophysin expression and neurite length, while high concentration of THC (1 µM) induced neurotoxicity. Glutamate caused the loss of neurons, reducing the number and the length of neurites. The high concentration of THC in the presence of glutamate caused the PAR accumulation in the condensed nuclei. Glutamate upregulated genes that are involved in synaptogenesis and excitatory signal cascade. Glutamate downregulated transcription of beta3 tubulin and microtubule-associated protein 2. THC partially regulated gene expression that is implicated in the neurogenesis and excitatory pathways. This suggests that CB1 receptors play a role in neurite growth and the low concentration of THC protects neurons during overexcitation, whereas the high concentration of THC enhances the neurotoxicity.
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Affiliation(s)
- Valentina L Savchenko
- The Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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22
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Al-Harrasi A, Behl T, Upadhyay T, Chigurupati S, Bhatt S, Sehgal A, Bhatia S, Singh S, Sharma N, Vijayabalan S, Palanimuthu VR, Das S, Kaur R, Aleya L, Bungau S. Targeting natural products against SARS-CoV-2. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:42404-42432. [PMID: 35362883 PMCID: PMC8972763 DOI: 10.1007/s11356-022-19770-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 03/13/2022] [Indexed: 06/01/2023]
Abstract
The human coronavirus disease (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Natural products, secondary metabolites show positive leads with antiviral and immunotherapy treatments using genomic studies in silico docking. In addition, it includes the action of a mechanism targeting the SARS-CoV-2. In this literature, we aimed to evaluate the antiviral movement of the NT-VRL-1 unique terpene definition to Human coronavirus (HCoV-229E). The effects of 19 hydrolysable tannins on the SARS-CoV-2 were therefore theoretically reviewed and analyzed utilising the molecular operating surroundings for their C-Like protease 3CLpro catalytic dyad residues Angiotensin converting enzyme-2 (MOE 09). Pedunculagin, tercatan, and castalin were detected as interacting strongly with SARS-receptor Cov-2's binding site and catalytic dyad (Cys145 and His41). SARS-CoV-2 methods of subunit S1 (ACE2) inhibit the interaction of the receiver with the s-protein once a drug molecule is coupled to the s-protein and prevent it from infecting the target cells in alkaloids. Our review strongly demonstrates the evidence that natural compounds and their derivatives can be used against the human coronavirus and serves as an area of research for future perspective.
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Affiliation(s)
- Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Birkat Al Mawz, Oman
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Tanuj Upadhyay
- Amity Institute of Pharmacy, Amity University, Gwalior, Madhya Pradesh, India
| | - Sridevi Chigurupati
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah, Kingdom of Saudi Arabia
| | - Shvetank Bhatt
- Amity Institute of Pharmacy, Amity University, Gwalior, Madhya Pradesh, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Center, University of Nizwa, Birkat Al Mawz, Oman
- School of Health Science, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Shantini Vijayabalan
- Faculty of Health and Medical Sciences, School of Pharmacy, Taylor's University, Subang Jaya, Kuala Lumpur, Malaysia
| | - Vasanth Raj Palanimuthu
- Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Suprava Das
- Department of Pharmacology, Faculty of Medicine, AIMST University, Semeling, Bedong, Kedah, Malaysia
| | - Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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23
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Lattke M, Guillemot F. Understanding astrocyte differentiation: Clinical relevance, technical challenges, and new opportunities in the omics era. WIREs Mech Dis 2022; 14:e1557. [PMID: 35546493 PMCID: PMC9539907 DOI: 10.1002/wsbm.1557] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 11/06/2022]
Abstract
Astrocytes are a major type of glial cells that have essential functions in development and homeostasis of the central nervous system (CNS). Immature astrocytes in the developing CNS support neuronal maturation and possess neural-stem-cell-like properties. Mature astrocytes partially lose these functions but gain new functions essential for adult CNS homeostasis. In pathological conditions, astrocytes become "reactive", which disrupts their mature homeostatic functions and reactivates some immature astrocyte-like properties, suggesting a partial reversal of astrocyte maturation. The loss of homeostatic astrocyte functions contributes to the pathogenesis of various neurological conditions, and therefore activating maturation-promoting mechanisms may be a promising therapeutic strategy to restore homeostasis. Manipulating the mechanisms underlying astrocyte maturation might also allow to facilitate CNS regeneration by enhancing developmental functions of adult astrocytes. However, such therapeutic strategies are still some distance away because of our limited understanding of astrocyte differentiation and maturation, due to biological and technical challenges, including the high degree of similarity of astrocytes with neural stem cells and the shortcomings of astrocyte markers. Current advances in systems biology have a huge potential to overcome these challenges. Recent transcriptomic analyses have already revealed new astrocyte markers and new regulators of astrocyte differentiation. However, the epigenomic changes that presumably occur during astrocyte differentiation remain an important, largely unexplored area for future research. Emerging technologies such as CRISPR/Cas9-based functional screens will further improve our understanding of the mechanisms underlying astrocyte differentiation. This may open up new clinical approaches to restore homeostasis in neurological disorders and/or promote CNS regeneration. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Stem Cells and Development Neurological Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Michael Lattke
- Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK
| | - Francois Guillemot
- Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK
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24
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Lee HG, Wheeler MA, Quintana FJ. Function and therapeutic value of astrocytes in neurological diseases. Nat Rev Drug Discov 2022; 21:339-358. [PMID: 35173313 PMCID: PMC9081171 DOI: 10.1038/s41573-022-00390-x] [Citation(s) in RCA: 278] [Impact Index Per Article: 92.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2022] [Indexed: 12/20/2022]
Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.
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Affiliation(s)
- Hong-Gyun Lee
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael A Wheeler
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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25
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Gerecke C, Egea Rodrigues C, Homann T, Kleuser B. The Role of Ten-Eleven Translocation Proteins in Inflammation. Front Immunol 2022; 13:861351. [PMID: 35386689 PMCID: PMC8977485 DOI: 10.3389/fimmu.2022.861351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/28/2022] [Indexed: 12/11/2022] Open
Abstract
Ten-eleven translocation proteins (TET1-3) are dioxygenases that oxidize 5-methyldeoxycytosine, thus taking part in passive and active demethylation. TETs have shown to be involved in immune cell development, affecting from self-renewal of stem cells and lineage commitment to terminal differentiation. In fact, dysfunction of TET proteins have been vastly associated with both myeloid and lymphoid leukemias. Recently, there has been accumulating evidence suggesting that TETs regulate immune cell function during innate and adaptive immune responses, thereby modulating inflammation. In this work, we pursue to review the current and recent evidence on the mechanistic aspects by which TETs regulate immune cell maturation and function. We will also discuss the complex interplay of TET expression and activity by several factors to modulate a multitude of inflammatory processes. Thus, modulating TET enzymes could be a novel pharmacological approach to target inflammation-related diseases and myeloid and lymphoid leukemias, when their activity is dysregulated.
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Affiliation(s)
- Christian Gerecke
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universität Berlin, Germany
| | - Caue Egea Rodrigues
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universität Berlin, Germany
| | - Thomas Homann
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universität Berlin, Germany
| | - Burkhard Kleuser
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Freie Universität Berlin, Germany
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26
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Kaplan G, Xu H, Abreu K, Feng J. DNA Epigenetics in Addiction Susceptibility. Front Genet 2022; 13:806685. [PMID: 35145550 PMCID: PMC8821887 DOI: 10.3389/fgene.2022.806685] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/06/2022] [Indexed: 12/22/2022] Open
Abstract
Addiction is a chronically relapsing neuropsychiatric disease that occurs in some, but not all, individuals who use substances of abuse. Relatively little is known about the mechanisms which contribute to individual differences in susceptibility to addiction. Neural gene expression regulation underlies the pathogenesis of addiction, which is mediated by epigenetic mechanisms, such as DNA modifications. A growing body of work has demonstrated distinct DNA epigenetic signatures in brain reward regions that may be associated with addiction susceptibility. Furthermore, factors that influence addiction susceptibility are also known to have a DNA epigenetic basis. In the present review, we discuss the notion that addiction susceptibility has an underlying DNA epigenetic basis. We focus on major phenotypes of addiction susceptibility and review evidence of cell type-specific, time dependent, and sex biased effects of drug use. We highlight the role of DNA epigenetics in these diverse processes and propose its contribution to addiction susceptibility differences. Given the prevalence and lack of effective treatments for addiction, elucidating the DNA epigenetic mechanism of addiction vulnerability may represent an expeditious approach to relieving the addiction disease burden.
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27
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Chern T, Achilleos A, Tong X, Hill MC, Saltzman AB, Reineke LC, Chaudhury A, Dasgupta SK, Redhead Y, Watkins D, Neilson JR, Thiagarajan P, Green JBA, Malovannaya A, Martin JF, Rosenblatt DS, Poché RA. Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy. Nat Commun 2022; 13:134. [PMID: 35013307 PMCID: PMC8748873 DOI: 10.1038/s41467-021-27759-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 12/13/2021] [Indexed: 12/26/2022] Open
Abstract
Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies. Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.
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Affiliation(s)
- Tiffany Chern
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Annita Achilleos
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA. .,Department of Basic and Clinical Sciences, University of Nicosia Medical School, Nicosia, Cyprus.
| | - Xuefei Tong
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Matthew C Hill
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alexander B Saltzman
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Lucas C Reineke
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Arindam Chaudhury
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Swapan K Dasgupta
- Department of Pathology, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, 77030, USA
| | - Yushi Redhead
- The Francis Crick Institute, London, NW1 1AT, UK.,Centre for Craniofacial Biology and Regeneration, King's College London, London, SE1 9RT, UK
| | - David Watkins
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada.,Division of Medical Biochemistry, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada
| | - Joel R Neilson
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Perumal Thiagarajan
- Department of Pathology, Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, 77030, USA.,Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jeremy B A Green
- Centre for Craniofacial Biology and Regeneration, King's College London, London, SE1 9RT, UK
| | - Anna Malovannaya
- Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - James F Martin
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.,Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.,Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA.,Texas Heart Institute, Houston, TX, 77030, USA
| | - David S Rosenblatt
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada.,Division of Medical Biochemistry, Department of Specialized Medicine, McGill University Health Centre, Montreal, QC, Canada.,Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Ross A Poché
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA. .,Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA. .,Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, 77030, USA.
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28
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Yildiz CB, Zimmer-Bensch G. Role of DNMTs in the Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:363-394. [DOI: 10.1007/978-3-031-11454-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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29
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Zeng Z, Lan T, Wei Y, Wei X. CCL5/CCR5 axis in human diseases and related treatments. Genes Dis 2022; 9:12-27. [PMID: 34514075 PMCID: PMC8423937 DOI: 10.1016/j.gendis.2021.08.004] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/08/2021] [Accepted: 08/12/2021] [Indexed: 02/05/2023] Open
Abstract
To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
| | - Tianxia Lan
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China
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30
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Araki R, Nishida S, Oishi Y, Tachioka H, Kita A, Yabe T. Methyl donor supplementation prevents a folate deficiency-induced depression-like state and neuronal immaturity of the dentate gyrus in mice. Neuroscience 2022; 485:12-22. [DOI: 10.1016/j.neuroscience.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/27/2021] [Accepted: 01/10/2022] [Indexed: 11/25/2022]
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31
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Achour M, Ferdousi F, Sasaki K, Isoda H. Luteolin Modulates Neural Stem Cells Fate Determination: In vitro Study on Human Neural Stem Cells, and in vivo Study on LPS-Induced Depression Mice Model. Front Cell Dev Biol 2021; 9:753279. [PMID: 34790666 PMCID: PMC8591246 DOI: 10.3389/fcell.2021.753279] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/11/2021] [Indexed: 11/23/2022] Open
Abstract
Luteolin is a natural flavone with neurotrophic effects observed on different neuronal cell lines. In the present study, we aimed to assess the effect of luteolin on hNSCs fate determination and the LPS-induced neuroinflammation in a mouse model of depression with astrocytogenesis defect. hNSCs were cultured in basal cell culture medium (control) or medium supplemented with luteolin or AICAR, a known inducer of astrogenesis. A whole-genome transcriptomic analysis showed that luteolin upregulated the expressions of genes related to neurotrophin, dopaminergic, hippo, and Wnt signaling pathways, and downregulated the genes involved in p53, TNF, FOXO, and Notch signaling pathways. We also found that astrocyte-specific gene GFAP, as well as other genes of the key signaling pathways involved in astrogenesis such as Wnt, BMP, and JAK-STAT pathways were upregulated in luteolin-treated hNSCs. On the other hand, neurogenesis and oligodendrogenesis-related genes, TUBB3, NEUROD 1 and 6, and MBP, were downregulated in luteolin-treated hNSCs. Furthermore, immunostaining showed that percentages of GFAP+ cells were significantly higher in luteolin- and AICAR-treated hNSCs compared to control hNSCs. Additionally, RT-qPCR results showed that luteolin upregulated the expressions of GFAP, BMP2, and STAT3, whereas the expression of TUBB3 remained unchanged. Next, we evaluated the effects of luteolin in LPS-induced mice model of depression that represents defects in astrocytogenesis. We found that oral administration of luteolin (10 mg/Kg) for eight consecutive days could decrease the immobility time on tail suspension test, a mouse behavioral test measuring depression-like behavior, and attenuate LPS-induced inflammatory responses by significantly decreasing IL-6 production in mice brain-derived astrocytes and serum, and TNFα and corticosterone levels in serum. Luteolin treatment also significantly increased mature BDNF, dopamine, and noradrenaline levels in the hypothalamus of LPS-induced depression mice. Though the behavioral effects of luteolin did not reach statistical significance, global gene expression analyses of mice hippocampus and brain-derived NSCs highlighted the modulatory effects of luteolin on different signaling pathways involved in the pathophysiology of depression. Altogether, our findings suggest an astrocytogenic potential of luteolin and its possible therapeutic benefits in neuroinflammatory and neurodegenerative diseases. However, further studies are required to identify the specific mechanism of action of luteolin.
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Affiliation(s)
- Mariem Achour
- Laboratory of Metabolic Biophysics and Applied Pharmacology, Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia.,Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan
| | - Farhana Ferdousi
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.,National Institute of Advanced Industrial Science and Technology (AIST)-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan
| | - Kazunori Sasaki
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.,National Institute of Advanced Industrial Science and Technology (AIST)-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.,National Institute of Advanced Industrial Science and Technology (AIST)-University of Tsukuba Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan
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32
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Reichard J, Zimmer-Bensch G. The Epigenome in Neurodevelopmental Disorders. Front Neurosci 2021; 15:776809. [PMID: 34803599 PMCID: PMC8595945 DOI: 10.3389/fnins.2021.776809] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/04/2021] [Indexed: 12/26/2022] Open
Abstract
Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.
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Affiliation(s)
- Julia Reichard
- Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, Aachen, Germany
| | - Geraldine Zimmer-Bensch
- Functional Epigenetics in the Animal Model, Institute for Biology II, RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 MultiSenses-MultiScales, Institute for Biology II, RWTH Aachen University, Aachen, Germany
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Takouda J, Katada S, Imamura T, Sanosaka T, Nakashima K. SoxE group transcription factor Sox8 promotes astrocytic differentiation of neural stem/precursor cells downstream of Nfia. Pharmacol Res Perspect 2021; 9:e00749. [PMID: 34677001 PMCID: PMC8532136 DOI: 10.1002/prp2.749] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 12/13/2022] Open
Abstract
The brain consists of three major cell types: neurons and two glial cell types (astrocytes and oligodendrocytes). Although they are generated from common multipotent neural stem/precursor cells (NS/PCs), embryonic NS/PCs cannot generate all of the cell types at the beginning of brain development. NS/PCs first undergo extensive self-renewal to expand their pools, and then acquire the potential to produce neurons, followed by glial cells. Astrocytes are the most frequently found cell type in the central nervous system (CNS), and play important roles in brain development and functions. Although it has been shown that nuclear factor IA (Nfia) is a pivotal transcription factor for conferring gliogenic potential on neurogenic NS/PCs by sequestering DNA methyltransferase 1 (Dnmt1) from astrocyte-specific genes, direct targets of Nfia that participate in astrocytic differentiation have yet to be completely identified. Here we show that SRY-box transcription factor 8 (Sox8) is a direct target gene of Nfia at the initiation of the gliogenic phase. We found that expression of Sox8 augmented leukemia inhibitory factor (LIF)-induced astrocytic differentiation, while Sox8 knockdown inhibited Nfia-enhanced astrocytic differentiation of NS/PCs. In contrast to Nfia, Sox8 did not induce DNA demethylation of an astrocyte-specific marker gene, glial fibrillary acidic protein (Gfap), but instead associated with LIF downstream transcription factor STAT3 through transcriptional coactivator p300, explaining how Sox8 expression further facilitated LIF-induced Gfap expression. Taken together, these results suggest that Sox8 is a crucial Nfia downstream transcription factor for the astrocytic differentiation of NS/PCs in the developing brain.
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Affiliation(s)
- Jun Takouda
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sayako Katada
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takuya Imamura
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Tsukasa Sanosaka
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Araki R, Nishida S, Nakajima Y, Iwakumo A, Tachioka H, Kita A, Yabe T. Low folate induces abnormal neuronal maturation and DNA hypomethylation of neuronal differentiation-related genes in cultured mouse neural stem and progenitor cells. Heliyon 2021; 7:e08071. [PMID: 34622073 PMCID: PMC8479244 DOI: 10.1016/j.heliyon.2021.e08071] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 02/05/2021] [Accepted: 09/22/2021] [Indexed: 11/28/2022] Open
Abstract
Folate deficiency in a fetus is well known to cause neurodevelopment defects and development disorders. A low level of folate is also thought to be a risk for depression in adults. We have previously shown that post-weaning low folate induces neuronal immaturity in the dentate gyrus in mice, which suggests that low folate causes neuropsychological disorders via inhibition of neuronal maturation. In this study, we examined the effects of low folate on expression and epigenetic modification of genes involved in neuronal differentiation and maturation in primary mouse neural stem/progenitor cells (NSPCs) in vitro. An increase in Nestin (NSPC marker)-positive cells was observed in cells differentiated in a low folate medium for 3 days. An increase in βIII-tubulin (Tuj1: immature neuron marker)-positive cells and a decrease in microtubule-associated protein 2 (MAP2: mature neuron marker)-positive cells were observed in cells differentiated in a low folate medium for 7 days. In these cells, mRNA levels for genes involved in neuronal differentiation and maturation were altered. Hypomethylation of DNA, but not of histone proteins, was also observed at some promoters of these neuronal genes. The level of S-adenosylmethionine (SAM), a methyl donor, was decreased in these cells. The abnormalities in neural maturation and changes in gene expression in culture under low folate conditions were partially normalized by addition of SAM (5 μM). Based on these results, decreased SAM may induce DNA hypomethylation at genes involved in neuronal differentiation and maturation under low folate conditions, and this hypomethylation may be associated with low folate-induced neuronal immaturity.
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Affiliation(s)
- Ryota Araki
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Shoji Nishida
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Yuki Nakajima
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Arimi Iwakumo
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Hayato Tachioka
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Ayami Kita
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
| | - Takeshi Yabe
- Laboratory of Functional Biomolecules and Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
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Abstract
Microglia are the resident immune cells of the central nervous system. Microglial progenitors are generated in the yolk sac during the early embryonic stage. Once microglia enter the brain primordium, these cells colonize the structure through migration and proliferation during brain development. Microglia account for a minor population among the total cells that constitute the developing cortex, but they can associate with many surrounding neural lineage cells by extending their filopodia and through their broad migration capacity. Of note, microglia change their distribution in a stage-dependent manner in the developing brain: microglia are homogenously distributed in the pallium in the early and late embryonic stages, whereas these cells are transiently absent from the cortical plate (CP) from embryonic day (E) 15 to E16 and colonize the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ). Previous studies have reported that microglia positioned in the VZ/SVZ/IZ play multiple roles in neural lineage cells, such as regulating neurogenesis, cell survival and neuronal circuit formation. In addition to microglial functions in the zones in which microglia are replenished, these cells indirectly contribute to the proper maturation of post-migratory neurons by exiting the CP during the mid-embryonic stage. Overall, microglial time-dependent distributional changes are necessary to provide particular functions that are required in specific regions. This review summarizes recent advances in the understanding of microglial colonization and multifaceted functions in the developing brain, especially focusing on the embryonic stage, and discuss the molecular mechanisms underlying microglial behaviors.
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Cheng W, Luo N, Zhang Y, Zhang X, Tan H, Zhang D, Sui J, Yue W, Yan H. DNA Methylation and Resting Brain Function Mediate the Association between Childhood Urbanicity and Better Speed of Processing. Cereb Cortex 2021; 31:4709-4718. [PMID: 33987663 PMCID: PMC8408435 DOI: 10.1093/cercor/bhab117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 01/10/2023] Open
Abstract
Urbanicity has been suggested to affect cognition, but the underlying mechanism remains unknown. We examined whether epigenetic modification (DNA methylation, DNAm), and brain white matter fiber integrity (fractional anisotropy, FA) or local spontaneous brain function activity (regional homogeneity, ReHo) play roles in the association between childhood urbanicity and cognition based on 497 healthy Chinese adults. We found significant correlation between childhood urbanicity and better cognitive performance. Multiset canonical correlation analysis (mCCA) identified an intercorrelated DNAm-FA-ReHo triplet, which showed significant pairwise correlations (DNAm-FA: Bonferroni-adjusted P, Pbon = 4.99E-03, rho = 0.216; DNAm-ReHo: Pbon = 4.08E-03, rho = 0.239; ReHo-FA: Pbon = 1.68E-06, rho = 0.328). Causal mediation analysis revealed that 1) ReHo mediated 10.86% childhood urbanicity effects on the speed of processing and 2) childhood urbanicity alters ReHo through DNA methylation in the cadherin and Wnt signaling pathways (mediated effect: 48.55%). The mediation effect of increased ReHo in the superior temporal gyrus underlying urbanicity impact on a better speed of processing was further validated in an independent cohort. Our work suggests a mediation role for ReHo, particularly increased brain activity in the superior temporal gyrus, in the urbanicity-associated speed of processing.
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Affiliation(s)
- Weiqiu Cheng
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
| | - Na Luo
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuyanan Zhang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
| | - Xiao Zhang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
| | - Haoyang Tan
- Lieber Institute for Brain Development, Baltimore, MD 21205, USA
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Dai Zhang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
- Tsinghua University-Peking University Joint Center for Life Sciences, Beijing 100871, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Jing Sui
- University of Chinese Academy of Sciences, Beijing 100049, China
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
| | - Weihua Yue
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
| | - Hao Yan
- Peking University Sixth Hospital/Institute of Mental Health, Beijing 100191, China
- NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
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Abbott LC, Nigussie F. Mercury Toxicity and Neurogenesis in the Mammalian Brain. Int J Mol Sci 2021; 22:ijms22147520. [PMID: 34299140 PMCID: PMC8305137 DOI: 10.3390/ijms22147520] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/12/2021] [Accepted: 07/05/2021] [Indexed: 01/21/2023] Open
Abstract
The mammalian brain is formed from billions of cells that include a wide array of neuronal and glial subtypes. Neural progenitor cells give rise to the vast majority of these cells during embryonic, fetal, and early postnatal developmental periods. The process of embryonic neurogenesis includes proliferation, differentiation, migration, the programmed death of some newly formed cells, and the final integration of differentiated neurons into neural networks. Adult neurogenesis also occurs in the mammalian brain, but adult neurogenesis is beyond the scope of this review. Developing embryonic neurons are particularly susceptible to neurotoxicants and especially mercury toxicity. This review focused on observations concerning how mercury, and in particular, methylmercury, affects neurogenesis in the developing mammalian brain. We summarized information on models used to study developmental mercury toxicity, theories of pathogenesis, and treatments that could be used to reduce the toxic effects of mercury on developing neurons.
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Affiliation(s)
- Louise C. Abbott
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX 77843-4458, USA
- Correspondence: ; Tel.: +1-541-254-0779
| | - Fikru Nigussie
- College of Veterinary Medicine, Oregon State University, 700 SW 30th Street, Corvallis, OR 97331, USA;
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Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury. Int J Mol Sci 2021; 22:ijms22136867. [PMID: 34206710 PMCID: PMC8268487 DOI: 10.3390/ijms22136867] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in nature. For example, astrocytes adapt to pathological conditions with a specific cellular response known as reactive astrogliosis, which includes extensive phenotypic and transcriptional changes. Reactive astrocytes may lose some of their homeostatic functions and gain protective or detrimental properties with great impact on damage propagation. Different astrocyte subpopulations seemingly coexist in reactive astrogliosis, however, the source of such heterogeneity is not completely understood. Altered cellular signaling in pathological compared to healthy conditions might be one source fueling astrocyte heterogeneity. Moreover, diversity might also be encoded cell-autonomously, for example as a result of astrocyte subtype specification during development. We hypothesize and propose here that elucidating the epigenetic signature underlying the phenotype of each astrocyte subtype is of high relevance to understand another regulative layer of astrocyte heterogeneity, in general as well as after injury or as a result of other pathological conditions. High resolution methods should allow enlightening diverse cell states and subtypes of astrocyte, their adaptation to pathological conditions and ultimately allow controlling and manipulating astrocyte functions in disease states. Here, we review novel literature reporting on astrocyte diversity from a developmental perspective and we focus on epigenetic signatures that might account for cell type specification.
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Hou J, Bi H, Ye Z, Huang W, Zou G, Zou X, Shi YS, Shen Y, Ma Q, Kirchhoff F, Hu Y, Chen G. Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System. J Neurosci 2021; 41:4976-4990. [PMID: 33972402 PMCID: PMC8197633 DOI: 10.1523/jneurosci.2455-19.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/30/2021] [Accepted: 04/28/2021] [Indexed: 11/21/2022] Open
Abstract
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.
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Affiliation(s)
- Jinxing Hou
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Huiru Bi
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Zhuoyang Ye
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Wenhui Huang
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany
| | - Gang Zou
- Department of General Surgery, Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Shenzhen, 518000, China
| | - Xiaochuan Zou
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Yun Stone Shi
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Ying Shen
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Quanhong Ma
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Second Affiliated Hospital, Soochow University, Suzhou, 215123, China
| | - Frank Kirchhoff
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany
| | - Yimin Hu
- Department of Anesthesiology, Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Guiquan Chen
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
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Rasheed M, Liang J, Wang C, Deng Y, Chen Z. Epigenetic Regulation of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2021; 22:4956. [PMID: 34066949 PMCID: PMC8125491 DOI: 10.3390/ijms22094956] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023] Open
Abstract
Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.
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Affiliation(s)
| | | | | | | | - Zixuan Chen
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (J.L.); (C.W.); (Y.D.)
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Vadodaria KC, Mendes APD, Mei A, Racha V, Erikson G, Shokhirev MN, Oefner R, Heard KJ, McCarthy MJ, Eyler L, Kelsoe JR, Santos R, Marchetto MC, Gage FH. Altered Neuronal Support and Inflammatory Response in Bipolar Disorder Patient-Derived Astrocytes. Stem Cell Reports 2021; 16:825-835. [PMID: 33667413 PMCID: PMC8072028 DOI: 10.1016/j.stemcr.2021.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
Bipolar disorder (BD) is characterized by cyclical mood shifts. Studies indicate that BD patients have a peripheral pro-inflammatory state and alterations in glial populations in the brain. We utilized an in vitro model to study inflammation-related phenotypes of astrocytes derived from induced pluripotent stem cells (iPSCs) generated from BD patients and healthy controls. BD astrocytes showed changes in transcriptome and induced a reduction in neuronal activity when co-cultured with neurons. IL-1β-stimulated BD astrocytes displayed a unique inflammatory gene expression signature and increased secretion of IL-6. Conditioned medium from stimulated BD astrocytes reduced neuronal activity, and this effect was partially blocked by IL-6 inactivating antibody. Our results suggest that BD astrocytes are functionally less supportive of neuronal excitability and this effect is partially mediated by IL-6. We confirmed higher IL-6 in blood in a distinct cohort of BD patients, highlighting the potential role of astrocyte-mediated inflammatory signaling in BD neuropathology.
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Affiliation(s)
- Krishna C Vadodaria
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Ana P D Mendes
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Arianna Mei
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Vipula Racha
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Galina Erikson
- The Razavi Newman Integrative Genomics and Bioinformatics Core (IGC), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Maxim N Shokhirev
- The Razavi Newman Integrative Genomics and Bioinformatics Core (IGC), The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Ruth Oefner
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Kelly J Heard
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA
| | - Michael J McCarthy
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
| | - Lisa Eyler
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
| | - John R Kelsoe
- Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA
| | - Renata Santos
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA; University of Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Dynamics of Neuronal Structure in Health and Disease, 102 rue de la Santé, 75014 Paris, France.
| | - Maria C Marchetto
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA; Department of Anthropology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
| | - Fred H Gage
- Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA.
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Sun J, Yang J, Miao X, Loh HH, Pei D, Zheng H. Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:7. [PMID: 33649938 PMCID: PMC7921253 DOI: 10.1186/s13619-020-00070-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/25/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain. MAIN BODY Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases. CONCLUSION Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.
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Affiliation(s)
- Jiaqi Sun
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China.
| | - Junzheng Yang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Xiaoli Miao
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Horace H Loh
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Duanqing Pei
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China.,CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China.,Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,School of Life Science, Westlake University, Hangzhou, 310024, China
| | - Hui Zheng
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China. .,CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. .,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China. .,Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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Qin L, Qiao C, Sheen V, Wang Y, Lu J. DNMT3L promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation independent of DNA methylation. Prog Neurobiol 2021; 201:102028. [PMID: 33636226 DOI: 10.1016/j.pneurobio.2021.102028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/10/2021] [Accepted: 02/21/2021] [Indexed: 01/13/2023]
Abstract
Previously, we reported global hypermethylation in DS might be attributed to the overexpression of HSA21 gene DNMT3L, which can enhance DNMT3A and DNMT3B activities in DNA methylation. To test this hypothesis, we compared the DNA methylation and RNA expression profiles of early-differentiated human neuroprogenitors with and without DNMT3L overexpression. We found DNMT3L overexpression only moderately increased the DNA methylation of limited genes, yet significantly altered global RNA expression of genes involved in neural differentiation. We further found that DNMT3L bound STAT1 or STAT3, and increased its phosphorylation and nuclear translocation, which in turn activated the expression of transcription factors including HES3, ASCL1, NEUROD2 and NEUROG2 and CDK inhibitor CDKN1A, which promoted cell cycle exit and neural differentiation. This phenomenon was also confirmed in Dnmt3l conditional knockin mice, which could be rescued by STAT1 and STAT3 phosphorylation inhibitors (Fludarabine and SH-4-54) but not DNA methylation inhibitor (Decitabine). These results suggest that DNMT3L play an important role during neurodevelopment independent of DNA methylation, which may contribute to the abnormal phenotypes observed in Down syndrome cortex.
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Affiliation(s)
- Lin Qin
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, 110122, China; Department of Obstetrics & Gynecology, Shenyang Women & Children's Hospital, Shenyang, Liaoning Province, 110121, China.
| | - Chong Qiao
- Department of Obstetrics & Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China.
| | - Volney Sheen
- Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
| | - Yu Wang
- Department of Obstetrics & Gynecology, Shenyang Women & Children's Hospital, Shenyang, Liaoning Province, 110121, China.
| | - Jie Lu
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, 110122, China.
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Sun D, Layman TS, Jeong H, Chatterjee P, Grogan K, Merritt JR, Maney DL, Yi SV. Genome-wide variation in DNA methylation linked to developmental stage and chromosomal suppression of recombination in white-throated sparrows. Mol Ecol 2021; 30:3453-3467. [PMID: 33421223 PMCID: PMC8359194 DOI: 10.1111/mec.15793] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/25/2020] [Accepted: 01/04/2021] [Indexed: 12/14/2022]
Abstract
Much of our knowledge on regulatory impacts of DNA methylation has come from laboratory‐bred model organisms, which may not exhibit the full extent of variation found in wild populations. Here, we investigated naturally‐occurring variation in DNA methylation in a wild avian species, the white‐throated sparrow (Zonotrichia albicollis). This species offers exceptional opportunities for studying the link between genetic differentiation and phenotypic traits because of a nonrecombining chromosome pair linked to both plumage and behavioural phenotypes. Using novel single‐nucleotide resolution methylation maps and gene expression data, we show that DNA methylation and the expression of DNA methyltransferases are significantly higher in adults than in nestlings. Genes for which DNA methylation varied between nestlings and adults were implicated in development and cell differentiation and were located throughout the genome. In contrast, differential methylation between plumage morphs was concentrated in the nonrecombining chromosome pair. Interestingly, a large number of CpGs on the nonrecombining chromosome, localized to transposable elements, have undergone dramatic loss of DNA methylation since the split of the ZAL2 and ZAL2m chromosomes. Changes in methylation predicted changes in gene expression for both chromosomes. In summary, we demonstrate changes in genome‐wide DNA methylation that are associated with development and with specific functional categories of genes in white‐throated sparrows. Moreover, we observe substantial DNA methylation reprogramming associated with the suppression of recombination, with implications for genome integrity and gene expression divergence. These results offer an unprecedented view of ongoing epigenetic reprogramming in a wild population. see also the Perspective by Jordan A. Anderson and Jenny Tung.
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Affiliation(s)
- Dan Sun
- School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.,Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA
| | - Thomas S Layman
- School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Hyeonsoo Jeong
- School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Paramita Chatterjee
- School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Kathleen Grogan
- Department of Psychology, Emory University, Atlanta, GA, USA
| | | | - Donna L Maney
- Department of Psychology, Emory University, Atlanta, GA, USA
| | - Soojin V Yi
- School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
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Pruvost M, Moyon S. Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination. Life (Basel) 2021; 11:62. [PMID: 33467699 PMCID: PMC7830029 DOI: 10.3390/life11010062] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 12/25/2022] Open
Abstract
Oligodendroglial cells are the myelinating cells of the central nervous system. While myelination is crucial to axonal activity and conduction, oligodendrocyte progenitor cells and oligodendrocytes have also been shown to be essential for neuronal support and metabolism. Thus, a tight regulation of oligodendroglial cell specification, proliferation, and myelination is required for correct neuronal connectivity and function. Here, we review the role of epigenetic modifications in oligodendroglial lineage cells. First, we briefly describe the epigenetic modalities of gene regulation, which are known to have a role in oligodendroglial cells. We then address how epigenetic enzymes and/or marks have been associated with oligodendrocyte progenitor specification, survival and proliferation, differentiation, and finally, myelination. We finally mention how environmental cues, in particular, neuronal signals, are translated into epigenetic modifications, which can directly influence oligodendroglial biology.
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Brenner M, Messing A. Regulation of GFAP Expression. ASN Neuro 2021; 13:1759091420981206. [PMID: 33601918 PMCID: PMC7897836 DOI: 10.1177/1759091420981206] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
Expression of the GFAP gene has attracted considerable attention because its onset is a marker for astrocyte development, its upregulation is a marker for reactive gliosis, and its predominance in astrocytes provides a tool for their genetic manipulation. The literature on GFAP regulation is voluminous, as almost any perturbation of development or homeostasis in the CNS will lead to changes in its expression. In this review, we limit our discussion to mechanisms proposed to regulate GFAP synthesis through a direct interaction with its gene or mRNA. Strengths and weaknesses of the supportive experimental findings are described, and suggestions made for additional studies. This review covers 15 transcription factors, DNA and histone methylation, and microRNAs. The complexity involved in regulating the expression of this intermediate filament protein suggests that GFAP function may vary among both astrocyte subtypes and other GFAP-expressing cells, as well as during development and in response to perturbations.
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Affiliation(s)
- Michael Brenner
- Department of Neurobiology, University of Alabama-Birmingham, Birmingham, Alabama, United States
| | - Albee Messing
- Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, United States
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States
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Unique and Specific m 6A RNA Methylation in Mouse Embryonic and Postnatal Cerebral Cortices. Genes (Basel) 2020; 11:genes11101139. [PMID: 32992647 PMCID: PMC7650744 DOI: 10.3390/genes11101139] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/16/2022] Open
Abstract
N6-methyladenosine (m6A)-mediated epitranscriptomic regulation is critical for various physiological processes. Genetic studies demonstrate that proper m6A-methylation is required for mouse brain development and function. Revealing landscapes of m6A-methylation in the cerebral cortex at different developmental stages will help to understand the biological meaning of epitranscriptomic regulation. Here, we depict the temporal-specific m6A-methylation status in mouse embryonic and postnatal cortices using methylated RNA immunoprecipitation (MeRIP) sequencing. We identified unique m6A binding motifs in stage-specific RNAs and found that more RNA transcripts are temporally methylated in embryonic cortices than in postnatal ones. Moreover, we found that cortical transcription factors and genes associated with neurological disorders are broadly as well specifically methylated at m6A sites. Our study highlights the importance of epitranscriptomic regulation in the developing cortex and provides a fundamental reference for future mechanistic examinations of m6A methylation-mediated gene expression regulation in normal brain development and neurological disorders.
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Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration. Int J Mol Sci 2020; 21:ijms21186875. [PMID: 32961703 PMCID: PMC7555074 DOI: 10.3390/ijms21186875] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.
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Linnerbauer M, Wheeler MA, Quintana FJ. Astrocyte Crosstalk in CNS Inflammation. Neuron 2020; 108:608-622. [PMID: 32898475 DOI: 10.1016/j.neuron.2020.08.012] [Citation(s) in RCA: 564] [Impact Index Per Article: 112.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/22/2022]
Abstract
Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
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Affiliation(s)
- Mathias Linnerbauer
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Wheeler
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Abstract
Adult stem cells undergo both replicative and chronological aging in their niches, with catastrophic declines in regenerative potential with age. Due to repeated environmental insults during aging, the chromatin landscape of stem cells erodes, with changes in both DNA and histone modifications, accumulation of damage, and altered transcriptional response. A body of work has shown that altered chromatin is a driver of cell fate changes and a regulator of self-renewal in stem cells and therefore a prime target for juvenescence therapeutics. This review focuses on chromatin changes in stem cell aging and provides a composite view of both common and unique epigenetic themes apparent from the studies of multiple stem cell types.
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Affiliation(s)
- Changyou Shi
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Lin Wang
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Payel Sen
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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