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1
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Hu M, Fan Z. Role and mechanisms of histone methylation in osteogenic/odontogenic differentiation of dental mesenchymal stem cells. Int J Oral Sci 2025; 17:24. [PMID: 40133254 PMCID: PMC11937254 DOI: 10.1038/s41368-025-00353-z] [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: 08/26/2024] [Revised: 01/01/2025] [Accepted: 02/11/2025] [Indexed: 03/27/2025] Open
Abstract
Dental mesenchymal stem cells (DMSCs) are pivotal for tooth development and periodontal tissue health and play an important role in tissue engineering and regenerative medicine because of their multidirectional differentiation potential and self-renewal ability. The cellular microenvironment regulates the fate of stem cells and can be modified using various optimization techniques. These methods can influence the cellular microenvironment, activate disparate signaling pathways, and induce different biological effects. "Epigenetic regulation" refers to the process of influencing gene expression and regulating cell fate without altering DNA sequences, such as histone methylation. Histone methylation modifications regulate pivotal transcription factors governing DMSCs differentiation into osteo-/odontogenic lineages. The most important sites of histone methylation in tooth organization were found to be H3K4, H3K9, and H3K27. Histone methylation affects gene expression and regulates stem cell differentiation by maintaining a delicate balance between major trimethylation sites, generating distinct chromatin structures associated with specific downstream transcriptional states. Several crucial signaling pathways associated with osteogenic differentiation are susceptible to modulation via histone methylation modifications. A deeper understanding of the regulatory mechanisms governing histone methylation modifications in osteo-/odontogenic differentiation and immune-inflammatory responses of DMSCs will facilitate further investigation of the epigenetic regulation of histone methylation in DMSC-mediated tissue regeneration and inflammation. Here is a concise overview of the pivotal functions of epigenetic histone methylation at H3K4, H3K9, and H3K27 in the regulation of osteo-/odontogenic differentiation and renewal of DMSCs in both non-inflammatory and inflammatory microenvironments. This review summarizes the current research on these processes in the context of tissue regeneration and therapeutic interventions.
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Affiliation(s)
- Meijun Hu
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Zhipeng Fan
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
- Research Unit of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing, China.
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2
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Carrillo-Cocom LM, Juárez-Méndez L, Rincón S, Rivera-Villanueva JM, Nic-Can GI, Zepeda A. Induction of cytotoxic effects and changes in DNA methylation-related gene expression in a human fibroblast cell line by the metal-organic framework [H 2NMe 2] 3 [Tb(III)(2,6 pyridinedicarboxylate) 3] (Tb-MOF). ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:46685-46696. [PMID: 36723839 DOI: 10.1007/s11356-023-25314-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 01/10/2023] [Indexed: 06/18/2023]
Abstract
Lanthanide metal-organic frameworks (lanthanide MOFs) may be utilized for a variety of environmental and human health applications due to their luminescent properties and high thermal and water stability. However, the cytotoxic and epigenetic effects produced in human cells are not known. Therefore, we evaluated the cytotoxic effects, internalization, and changes in the mRNA abundance of DNA methylation and demethylation enzymes by exposing human fibroblast cells to a metal-organic framework [H2NMe2]3 [Tb(III)(2,6 pyridinedicarboxylate)3] (Tb-MOF). For this purpose, the cells were exposed to six concentrations (0.05 to 1.6 mg/mL) of Tb-MOF for 48 h. Field emission electron microscopy coupled to linear energy dispersive spectroscopy (FESEM‒EDS) and confocal microscopy analysis were performed. The cytotoxicity was determined with crystal violet and MTT assays. The results demonstrated the internalization of Tb-MOF at concentrations as low as 0.05 mg/mL, as well as concentration-dependent toxicity. Additionally, we detected significant changes in the gene expression levels of DNA methyltransferases and demethylases due to the presence of Tb-MOF, suggesting that Tb-MOF could generate epigenetic changes even at low concentrations. The results of our study may establish a foundation for future research attempting to develop and apply secure nanomaterials (e.g., MOFs) to minimize damage to the environment and human health.
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Affiliation(s)
- Leydi Maribel Carrillo-Cocom
- Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Campus de Ingenierías y Ciencias Exactas, periférico norte km 33.5, C.P. 97203, Mérida, Yucatán, México
| | - Lucia Juárez-Méndez
- Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Campus de Ingenierías y Ciencias Exactas, periférico norte km 33.5, C.P. 97203, Mérida, Yucatán, México
| | - Susana Rincón
- Tecnológico Nacional de México/I.T. Mérida, Av. Tecnológico S/N, C.P. 97118, Mérida, Yucatán, México
| | - José María Rivera-Villanueva
- Facultad de Ciencias Químicas, Universidad Veracruzana, prolongación oriente 6 No. 1009. Colonia Rafael Alvarado, C.P. 94340, Orizaba, Veracruz, México
| | - Geovanny Iran Nic-Can
- CONACYT-Universidad Autónoma de Yucatán. Facultad de Ingeniería Química, Campus de Ingenierías y Ciencias Exactas, periférico norte km 33.5, C.P. 97203, Mérida, Yucatán, México
| | - Alejandro Zepeda
- Facultad de Ingeniería Química, Universidad Autónoma de Yucatán, Campus de Ingenierías y Ciencias Exactas, periférico norte km 33.5, C.P. 97203, Mérida, Yucatán, México.
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3
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Targeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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4
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Distinct interactors define the p63 transcriptional signature in epithelial development or cancer. Biochem J 2022; 479:1375-1392. [PMID: 35748701 PMCID: PMC9250260 DOI: 10.1042/bcj20210737] [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: 04/05/2022] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022]
Abstract
The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.
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5
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Argaez-Sosa AA, Rodas-Junco BA, Carrillo-Cocom LM, Rojas-Herrera RA, Coral-Sosa A, Aguilar-Ayala FJ, Aguilar-Pérez D, Nic-Can GI. Higher Expression of DNA (de)methylation-Related Genes Reduces Adipogenicity in Dental Pulp Stem Cells. Front Cell Dev Biol 2022; 10:791667. [PMID: 35281092 PMCID: PMC8907981 DOI: 10.3389/fcell.2022.791667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 02/08/2022] [Indexed: 12/17/2022] Open
Abstract
Obesity is a significant health concern that has reached alarming proportions worldwide. The overconsumption of high-energy foods may cause metabolic dysfunction and promote the generation of new adipocytes by contributing to several obesity-related diseases. Such concerns demand a deeper understanding of the origin of adipocytes if we want to develop new therapeutic approaches. Recent findings indicate that adipocyte development is facilitated by tight epigenetic reprogramming, which is required to activate the gene program to change the fate of mesenchymal stem cells (MSCs) into mature adipocytes. Like adipose tissue, different tissues are also potential sources of adipocyte-generating MSCs, so it is interesting to explore whether the epigenetic mechanisms of adipogenic differentiation vary from one depot to another. To investigate how DNA methylation (an epigenetic mark that plays an essential role in controlling transcription and cellular differentiation) contributes to adipogenic potential, dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PLSCs) were analyzed during adipogenic differentiation in vitro. Here, we show that the capacity to differentiate from DPSCs or PLSCs to adipocytes may be associated with the expression pattern of DNA methylation-related genes acquired during the induction of the adipogenic program. Our study provides insights into the details of DNA methylation during the adipogenic determination of dental stem cells, which can be a starting point to identify the factors that affect the differentiation of these cells and provide new strategies to regulate differentiation and adipocyte expansion.
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Affiliation(s)
- Adaylu A. Argaez-Sosa
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Beatriz A. Rodas-Junco
- Laboratorio Translacional de Células Troncales, Facultad de Odontología, Universidad Autónoma de Yucatán, Mérida, Mexico
- CONACYT-Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Leydi M. Carrillo-Cocom
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Rafael A. Rojas-Herrera
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Abel Coral-Sosa
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Fernando J. Aguilar-Ayala
- Laboratorio Translacional de Células Troncales, Facultad de Odontología, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - David Aguilar-Pérez
- Laboratorio Translacional de Células Troncales, Facultad de Odontología, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Geovanny I. Nic-Can
- Laboratorio Translacional de Células Troncales, Facultad de Odontología, Universidad Autónoma de Yucatán, Mérida, Mexico
- CONACYT-Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
- *Correspondence: Geovanny I. Nic-Can, ,
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6
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Key Markers and Epigenetic Modifications of Dental-Derived Mesenchymal Stromal Cells. Stem Cells Int 2021; 2021:5521715. [PMID: 34046069 PMCID: PMC8128613 DOI: 10.1155/2021/5521715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/08/2021] [Accepted: 04/17/2021] [Indexed: 12/13/2022] Open
Abstract
As a novel research hotspot in tissue regeneration, dental-derived mesenchymal stromal cells (MSCs) are famous for their accessibility, multipotent differentiation ability, and high proliferation. However, cellular heterogeneity is a major obstacle to the clinical application of dental-derived MSCs. Here, we reviewed the heterogeneity of dental-derived MSCs firstly and then discussed the key markers and epigenetic modifications related to the proliferation, differentiation, immunomodulation, and aging of dental-derived MSCs. These messages help to control the composition and function of dental-derived MSCs and thus accelerate the translation of cell therapy into clinical practice.
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7
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Wang Z, Wang X, Bi M, Hu X, Wang Q, Liang H, Liu D. Effects of the histone acetylase inhibitor C646 on growth and differentiation of adipose-derived stem cells. Cell Cycle 2021; 20:392-405. [PMID: 33487075 DOI: 10.1080/15384101.2021.1876389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
As an important histone acetylase, the transcriptional coactivator P300/CBP affects target gene expression and plays a role in the maintenance of stem cell characteristics and differentiation potential. In this study, we explored the action of a highly effective selective histone acetylase inhibitor, C646, on goat adipose-derived stem cells (gADSCs), and investigated the impact of histone acetylation on the growth characteristics and the differentiation potential of ADSCs. We found that C646 blocked the cell proliferation, arrested the cell cycle, and triggered apoptosis. Notably, immunocytochemistry and western blot analyses showed that the acetylation level of histone H3K9 was increased. Moreover, although real-time quantitative PCR and western blot confirmed that P300 expression was inhibited under these conditions, the expression level of two other histone acetylases, TIP60 and PCAF, was significantly increased. Furthermore, C646 clearly promoted the differentiation of gADSCs into adipocytes and had an impact on their differentiation into neuronal cells. This study provides new insights into the epigenetic regulation of stem cell differentiation and may represent an experimental basis for the comprehension of stem cell characteristics and function. Furthermore, it is of great relevance for the application of adult stem cells to somatic cell cloning, which may improve the efficiency of large livestock cloning and foster the production of transgenic animals.
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Affiliation(s)
- Zhimin Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Xiao Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Meiyu Bi
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Xiao Hu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Qing Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Hao Liang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
| | - Dongjun Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University , Hohhot, P.R, China
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8
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Jayarajan J, Milsom MD. The role of the stem cell epigenome in normal aging and rejuvenative therapy. Hum Mol Genet 2020; 29:R236-R247. [PMID: 32744315 DOI: 10.1093/hmg/ddaa167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 12/21/2022] Open
Abstract
Adult stem cells are ultimately responsible for the lifelong maintenance of regenerating of tissues during both homeostasis and following injury. Hence, the functional attrition of adult stem cells is thought to be an important driving factor behind the progressive functional decline of tissues and organs that is observed during aging. The mechanistic cause underlying this age-associated exhaustion of functional stem cells is likely to be complex and multifactorial. However, it is clear that progressive remodeling of the epigenome and the resulting deregulation of gene expression programs can be considered a hallmark of aging, and is likely a key factor in mediating altered biological function of aged stem cells. In this review, we outline cell intrinsic and extrinsic mediators of epigenome remodeling during aging; discuss how such changes can impact on stem cell function; and describe how resetting the aged epigenome may rejuvenate some of the biological characteristics of stem cells.
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Affiliation(s)
- Jeyan Jayarajan
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Michael D Milsom
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM).,DKFZ-ZMBH Alliance, Heidelberg, Germany
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9
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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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10
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Bobkova NV, Poltavtseva RA, Leonov SV, Sukhikh GT. Neuroregeneration: Regulation in Neurodegenerative Diseases and Aging. BIOCHEMISTRY (MOSCOW) 2020; 85:S108-S130. [PMID: 32087056 DOI: 10.1134/s0006297920140060] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It had been commonly believed for a long time, that once established, degeneration of the central nervous system (CNS) is irreparable, and that adult person merely cannot restore dead or injured neurons. The existence of stem cells (SCs) in the mature brain, an organ with minimal regenerative ability, had been ignored for many years. Currently accepted that specific structures of the adult brain contain neural SCs (NSCs) that can self-renew and generate terminally differentiated brain cells, including neurons and glia. However, their contribution to the regulation of brain activity and brain regeneration in natural aging and pathology is still a subject of ongoing studies. Since the 1970s, when Fuad Lechin suggested the existence of repair mechanisms in the brain, new exhilarating data from scientists around the world have expanded our knowledge on the mechanisms implicated in the generation of various cell phenotypes supporting the brain, regulation of brain activity by these newly generated cells, and participation of SCs in brain homeostasis and regeneration. The prospects of the SC research are truthfully infinite and hitherto challenging to forecast. Once researchers resolve the issues regarding SC expansion and maintenance, the implementation of the SC-based platform could help to treat tissues and organs impaired or damaged in many devastating human diseases. Over the past 10 years, the number of studies on SCs has increased exponentially, and we have already become witnesses of crucial discoveries in SC biology. Comprehension of the mechanisms of neurogenesis regulation is essential for the development of new therapeutic approaches for currently incurable neurodegenerative diseases and neuroblastomas. In this review, we present the latest achievements in this fast-moving field and discuss essential aspects of NSC biology, including SC regulation by hormones, neurotransmitters, and transcription factors, along with the achievements of genetic and chemical reprogramming for the safe use of SCs in vitro and in vivo.
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Affiliation(s)
- N V Bobkova
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia.
| | - R A Poltavtseva
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. .,National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov, Ministry of Healthcare of Russian Federation, Moscow, 117997, Russia
| | - S V Leonov
- Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia. .,Moscow Institute of Physics and Technology (National Research University), The Phystech School of Biological and Medical Physics, Dolgoprudny, Moscow Region, 141700, Russia
| | - G T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov, Ministry of Healthcare of Russian Federation, Moscow, 117997, Russia.
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11
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Khaminets A, Ronnen-Oron T, Baldauf M, Meier E, Jasper H. Cohesin controls intestinal stem cell identity by maintaining association of Escargot with target promoters. eLife 2020; 9:e48160. [PMID: 32022682 PMCID: PMC7002041 DOI: 10.7554/elife.48160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 01/18/2020] [Indexed: 12/27/2022] Open
Abstract
Intestinal stem cells (ISCs) maintain regenerative capacity of the intestinal epithelium. Their function and activity are regulated by transcriptional changes, yet how such changes are coordinated at the genomic level remains unclear. The Cohesin complex regulates transcription globally by generating topologically-associated DNA domains (TADs) that link promotor regions with distant enhancers. We show here that the Cohesin complex prevents premature differentiation of Drosophila ISCs into enterocytes (ECs). Depletion of the Cohesin subunit Rad21 and the loading factor Nipped-B triggers an ISC to EC differentiation program that is independent of Notch signaling, but can be rescued by over-expression of the ISC-specific escargot (esg) transcription factor. Using damID and transcriptomic analysis, we find that Cohesin regulates Esg binding to promoters of differentiation genes, including a group of Notch target genes involved in ISC differentiation. We propose that Cohesin ensures efficient Esg-dependent gene repression to maintain stemness and intestinal homeostasis.
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Affiliation(s)
| | | | - Maik Baldauf
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)JenaGermany
| | - Elke Meier
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)JenaGermany
| | - Heinrich Jasper
- Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)JenaGermany
- Buck Institute for Research on AgingNovatoUnited States
- Immunology DiscoveryGenentech, IncSouth San FranciscoUnited States
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12
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Zhao W, Wang Y, Liang FS. Chemical and Light Inducible Epigenome Editing. Int J Mol Sci 2020; 21:ijms21030998. [PMID: 32028669 PMCID: PMC7037166 DOI: 10.3390/ijms21030998] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 01/30/2020] [Accepted: 01/30/2020] [Indexed: 12/22/2022] Open
Abstract
The epigenome defines the unique gene expression patterns and resulting cellular behaviors in different cell types. Epigenome dysregulation has been directly linked to various human diseases. Epigenome editing enabling genome locus-specific targeting of epigenome modifiers to directly alter specific local epigenome modifications offers a revolutionary tool for mechanistic studies in epigenome regulation as well as the development of novel epigenome therapies. Inducible and reversible epigenome editing provides unique temporal control critical for understanding the dynamics and kinetics of epigenome regulation. This review summarizes the progress in the development of spatiotemporal-specific tools using small molecules or light as inducers to achieve the conditional control of epigenome editing and their applications in epigenetic research.
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13
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Mortimer T, Wainwright EN, Patel H, Siow BM, Jaunmuktane Z, Brandner S, Scaffidi P. Redistribution of EZH2 promotes malignant phenotypes by rewiring developmental programmes. EMBO Rep 2019; 20:e48155. [PMID: 31468686 PMCID: PMC6776892 DOI: 10.15252/embr.201948155] [Citation(s) in RCA: 11] [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: 03/22/2019] [Revised: 08/05/2019] [Accepted: 08/08/2019] [Indexed: 01/08/2023] Open
Abstract
Epigenetic regulators are often hijacked by cancer cells to sustain malignant phenotypes. How cells repurpose key regulators of cell identity as tumour-promoting factors is unclear. The antithetic role of the Polycomb component EZH2 in normal brain and glioma provides a paradigm to dissect how wild-type chromatin modifiers gain a pathological function in cancer. Here, we show that oncogenic signalling induces redistribution of EZH2 across the genome, and through misregulation of homeotic genes corrupts the identity of neural cells. Characterisation of EZH2 targets in de novo transformed cells, combined with analysis of glioma patient datasets and cell lines, reveals that acquisition of tumorigenic potential is accompanied by a transcriptional switch involving de-repression of spinal cord-specifying HOX genes and concomitant silencing of the empty spiracles homologue EMX2, a critical regulator of neurogenesis in the forebrain. Maintenance of tumorigenic potential by glioblastoma cells requires EMX2 repression, since forced EMX2 expression prevents tumour formation. Thus, by redistributing EZH2 across the genome, cancer cells subvert developmental transcriptional programmes that specify normal cell identity and remove physiological breaks that restrain cell proliferation.
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MESH Headings
- Animals
- Carcinogenesis/genetics
- Carcinogenesis/pathology
- Cell Line, Tumor
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Chromatin/metabolism
- DNA Methylation/genetics
- Enhancer of Zeste Homolog 2 Protein/metabolism
- Gene Expression Regulation, Neoplastic
- Genes, Homeobox
- Glioma/genetics
- Glioma/pathology
- Humans
- Male
- Mice, Inbred NOD
- Models, Biological
- Phenotype
- Protein Binding
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Transcription, Genetic
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Affiliation(s)
- Thomas Mortimer
- Cancer Epigenetics LaboratoryThe Francis Crick InstituteLondonUK
| | | | - Harshil Patel
- Bioinformatics and BiostatisticsThe Francis Crick InstituteLondonUK
| | | | - Zane Jaunmuktane
- Department of Clinical and Movement NeurosciencesQueen Square Brain BankUCL Queen Square Institute of NeurologyLondonUK
- Division of NeuropathologyNational Hospital for Neurology and NeurosurgeryUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Sebastian Brandner
- Division of NeuropathologyNational Hospital for Neurology and NeurosurgeryUniversity College London Hospitals NHS Foundation TrustLondonUK
- Department of Neurodegenerative DiseaseUCL Queen Square Institute of NeurologyLondonUK
| | - Paola Scaffidi
- Cancer Epigenetics LaboratoryThe Francis Crick InstituteLondonUK
- UCL Cancer InstituteUniversity College LondonLondonUK
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14
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Cruciani S, Santaniello S, Montella A, Ventura C, Maioli M. Orchestrating stem cell fate: Novel tools for regenerative medicine. World J Stem Cells 2019; 11:464-475. [PMID: 31523367 PMCID: PMC6716083 DOI: 10.4252/wjsc.v11.i8.464] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 05/28/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells are undifferentiated cells able to acquire different phenotypes under specific stimuli. In vitro manipulation of these cells is focused on understanding stem cell behavior, proliferation and pluripotency. Latest advances in the field of stem cells concern epigenetics and its role in maintaining self-renewal and differentiation capabilities. Chemical and physical stimuli can modulate cell commitment, acting on gene expression of Oct-4, Sox-2 and Nanog, the main stemness markers, and tissue-lineage specific genes. This activation or repression is related to the activity of chromatin-remodeling factors and epigenetic regulators, new targets of many cell therapies. The aim of this review is to afford a view of the current state of in vitro and in vivo stem cell applications, highlighting the strategies used to influence stem cell commitment for current and future cell therapies. Identifying the molecular mechanisms controlling stem cell fate could open up novel strategies for tissue repairing processes and other clinical applications.
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Affiliation(s)
- Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, Consiglio Nazionale delle Ricerche, Bologna 40129, Italy
| | - Sara Santaniello
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, Consiglio Nazionale delle Ricerche, Bologna 40129, Italy
| | - Andrea Montella
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
- Operative Unit of Clinical Genetics and Developmental Biology, Sassari 07100, Italy
| | - Carlo Ventura
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, Consiglio Nazionale delle Ricerche, Bologna 40129, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems – Eldor Lab, Innovation Accelerator, Consiglio Nazionale delle Ricerche, Bologna 40129, Italy
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari 09042, Italy
- Center for Developmental Biology and Reprogramming-CEDEBIOR, Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy
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15
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Xie ZY, Wang P, Wu YF, Shen HY. Long non-coding RNA: The functional regulator of mesenchymal stem cells. World J Stem Cells 2019; 11:167-179. [PMID: 30949295 PMCID: PMC6441937 DOI: 10.4252/wjsc.v11.i3.167] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/07/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases. Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA (LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently, multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.
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Affiliation(s)
- Zhong-Yu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Yan-Feng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong Province, China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
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16
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Epigenetic Regulation of Skin Cells in Natural Aging and Premature Aging Diseases. Cells 2018; 7:cells7120268. [PMID: 30545089 PMCID: PMC6315602 DOI: 10.3390/cells7120268] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/07/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023] Open
Abstract
Skin undergoes continuous renewal throughout an individual’s lifetime relying on stem cell functionality. However, a decline of the skin regenerative potential occurs with age. The accumulation of senescent cells over time probably reduces tissue regeneration and contributes to skin aging. Keratinocytes and dermal fibroblasts undergo senescence in response to several intrinsic or extrinsic stresses, including telomere shortening, overproduction of reactive oxygen species, diet, and sunlight exposure. Epigenetic mechanisms directly regulate skin homeostasis and regeneration, but they also mark cell senescence and the natural and pathological aging processes. Progeroid syndromes represent a group of clinical and genetically heterogeneous pathologies characterized by the accelerated aging of various tissues and organs, including skin. Skin cells from progeroid patients display molecular hallmarks that mimic those associated with naturally occurring aging. Thus, investigations on progeroid syndromes strongly contribute to disclose the causal mechanisms that underlie the aging process. In the present review, we discuss the role of epigenetic pathways in skin cell regulation during physiologic and premature aging.
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17
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Singer D, Thamm K, Zhuang H, Karbanová J, Gao Y, Walker JV, Jin H, Wu X, Coveney CR, Marangoni P, Lu D, Grayson PRC, Gulsen T, Liu KJ, Ardu S, Wann AK, Luo S, Zambon AC, Jetten AM, Tredwin C, Klein OD, Attanasio M, Carmeliet P, Huttner WB, Corbeil D, Hu B. Prominin-1 controls stem cell activation by orchestrating ciliary dynamics. EMBO J 2018; 38:embj.201899845. [PMID: 30523147 PMCID: PMC6331727 DOI: 10.15252/embj.201899845] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 01/09/2023] Open
Abstract
Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.
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Affiliation(s)
- Donald Singer
- Peninsula Dental School, University of Plymouth, Plymouth, UK
| | - Kristina Thamm
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Heng Zhuang
- Peninsula Dental School, University of Plymouth, Plymouth, UK.,Department of Cariology, Endodontology and Operative Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Yan Gao
- Peninsula Dental School, University of Plymouth, Plymouth, UK.,Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | | | - Heng Jin
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.,Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiangnan Wu
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA
| | - Clarissa R Coveney
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute, Nuffield Department for Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Pauline Marangoni
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA
| | - Dongmei Lu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Tulay Gulsen
- Peninsula Dental School, University of Plymouth, Plymouth, UK
| | - Karen J Liu
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
| | - Stefano Ardu
- Division of Cariology & Endodontology, Dental School, University of Geneva, Geneva, Switzerland
| | - Angus Kt Wann
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute, Nuffield Department for Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Shouqing Luo
- Peninsula Medical School, University of Plymouth, Plymouth, UK
| | | | - Anton M Jetten
- Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | | | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.,Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, CA, USA
| | - Massimo Attanasio
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
| | - Peter Carmeliet
- Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, Leuven, Belgium.,VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
| | - Wieland B Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center and Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany
| | - Bing Hu
- Peninsula Dental School, University of Plymouth, Plymouth, UK
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18
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Genome-Wide DNA Methylation Analysis during Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:8238496. [PMID: 30275838 PMCID: PMC6151374 DOI: 10.1155/2018/8238496] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/06/2018] [Accepted: 08/13/2018] [Indexed: 12/14/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) nowadays are regarded as promising candidates in cell-based therapy for the regeneration of damaged bone tissues that are either incurable or intractable due to the insufficiency of current therapies. Recent studies suggest that BMSCs differentiate into osteoblasts, and that this differentiation is regulated by some specific patterns of epigenetic modifications, such as DNA methylation. However, the potential role of DNA methylation modification in BMSC osteogenic differentiation is unclear. In this study, we performed a genome-wide study of DNA methylation between the noninduced and induced osteogenic differentiation of BMSCs at day 7. We found that the majority of cytosines in a CpG context were methylated in induced BMSCs. Our results also revealed that, along with the induced osteogenic differentiation in BMSCs, the average genomic methylation levels and CpG methylation in transcriptional factor regions (TFs) were increased, the CpG methylation level of various genomic elements was mainly in the medium-high methylation section, and CpG methylation levels in the repeat element had highly methylated levels. The GO analysis of differentially methylated region- (DMR-) associated genes (DMGs) showed that GO terms, including cytoskeletal protein binding (included in Molecular Function GO terms), skeletal development (included in Biological Process GO terms), mesenchymal cell differentiation (included in Biological Process GO terms), and stem cell differentiation (included in Biological Process), were enriched in the hypermethylated DMGs. Then, the KEGG analysis results showed that the WNT pathway, inositol phosphate metabolism pathway, and cocaine addiction pathway were more correlative with the DMRs during the induced osteogenic differentiation in BMSCs. In conclusion, this study revealed the difference of methylated levels during the noninduced and induced osteogenic differentiation of BMSCs and provided useful information for future works to characterize the important function of epigenetic mechanisms on BMSCs' differentiation.
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19
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Pascual G, Domínguez D, Benitah SA. The contributions of cancer cell metabolism to metastasis. Dis Model Mech 2018; 11:11/8/dmm032920. [PMID: 29739810 PMCID: PMC6124557 DOI: 10.1242/dmm.032920] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metastasis remains the leading cause of cancer-related deaths worldwide, and our inability to identify the tumour cells that colonize distant sites hampers the development of effective anti-metastatic therapies. However, with recent research advances we are beginning to distinguish metastasis-initiating cells from their non-metastatic counterparts. Importantly, advances in genome sequencing indicate that the acquisition of metastatic competency does not involve the progressive accumulation of driver mutations; moreover, in the early stages of tumorigenesis, cancer cells harbour combinations of driver mutations that endow them with metastatic competency. Novel findings highlight that cells can disseminate to distant sites early during primary tumour growth, remaining dormant and untreatable for long periods before metastasizing. Thus, metastatic cells must require local and systemic influences to generate metastases. This hypothesis suggests that factors derived from our lifestyle, such as our diet, exert a strong influence on tumour progression, and that such factors could be modulated if understood. Here, we summarize the recent findings on how specific metabolic cues modulate the behaviour of metastatic cells and how they influence the genome and epigenome of metastatic cells. We also discuss how crosstalk between metabolism and the epigenome can be harnessed to develop new anti-metastatic therapies.
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Affiliation(s)
- Gloria Pascual
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
| | - Diana Domínguez
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), Oncology Department, The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain .,Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain
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20
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Rodas-Junco BA, Canul-Chan M, Rojas-Herrera RA, De-la-Peña C, Nic-Can GI. Stem Cells from Dental Pulp: What Epigenetics Can Do with Your Tooth. Front Physiol 2017; 8:999. [PMID: 29270128 PMCID: PMC5724083 DOI: 10.3389/fphys.2017.00999] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 11/20/2017] [Indexed: 12/16/2022] Open
Abstract
Adult stem cells have attracted scientific attention because they are able to self-renew and differentiate into several specialized cell types. In this context, human dental tissue-derived mesenchymal stem cells (hDT-MSCs) have emerged as a possible solution for repairing or regenerating damaged tissues. These cells can be isolated from primary teeth that are naturally replaced, third molars, or other dental tissues and exhibit self-renewal, a high proliferative rate and a great multilineage potential. However, the cellular and molecular mechanisms that determine lineage specification are still largely unknown. It is known that a change in cell fate requires the deletion of existing transcriptional programs, followed by the establishment of a new developmental program to give rise to a new cell lineage. Increasing evidence indicates that chromatin structure conformation can influence cell fate. In this way, reversible chemical modifications at the DNA or histone level, and combinations thereof can activate or inactivate cell-type-specific gene sequences, giving rise to an alternative cell fates. On the other hand, miRNAs are starting to emerge as a possible player in establishing particular somatic lineages. In this review, we discuss two new and promising research fields in medicine and biology, epigenetics and stem cells, by summarizing the properties of hDT-MSCs and highlighting the recent findings on epigenetic contributions to the regulation of cellular differentiation.
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Affiliation(s)
- Beatriz A Rodas-Junco
- CONACYT-Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Michel Canul-Chan
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Rafael A Rojas-Herrera
- Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
| | - Clelia De-la-Peña
- Unidad de Biotecnología, Centro de Investigación Científica de Yucatán, Mérida, Mexico
| | - Geovanny I Nic-Can
- CONACYT-Facultad de Ingeniería Química, Campus de Ciencias Exactas e Ingeniería, Universidad Autónoma de Yucatán, Mérida, Mexico
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21
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Rinaldi L, Avgustinova A, Martín M, Datta D, Solanas G, Prats N, Benitah SA. Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-γ. eLife 2017; 6:e21697. [PMID: 28425913 PMCID: PMC5429093 DOI: 10.7554/elife.21697] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 04/13/2017] [Indexed: 12/12/2022] Open
Abstract
The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here, we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers and inhibits the expression of lipid metabolism genes, including PPAR-γ, by directly methylating their promoters. Importantly, inhibition of PPAR-γ partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis and that squamous carcinomas are sensitive to inhibition of PPAR-γ.
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Affiliation(s)
- Lorenzo Rinaldi
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
| | - Alexandra Avgustinova
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mercè Martín
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Debayan Datta
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Guiomar Solanas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Neus Prats
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
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22
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Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A, Blanco E, Pons JI, Matallanas D, Von Kriegsheim A, Di Croce L, Benitah SA. Dnmt3a and Dnmt3b Associate with Enhancers to Regulate Human Epidermal Stem Cell Homeostasis. Cell Stem Cell 2016; 19:491-501. [PMID: 27476967 DOI: 10.1016/j.stem.2016.06.020] [Citation(s) in RCA: 160] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 04/25/2016] [Accepted: 06/29/2016] [Indexed: 12/22/2022]
Abstract
The genome-wide localization and function of endogenous Dnmt3a and Dnmt3b in adult stem cells are unknown. Here, we show that in human epidermal stem cells, the two proteins bind in a histone H3K36me3-dependent manner to the most active enhancers and are required to produce their associated enhancer RNAs. Both proteins prefer super-enhancers associated to genes that either define the ectodermal lineage or establish the stem cell and differentiated states. However, Dnmt3a and Dnmt3b differ in their mechanisms of enhancer regulation: Dnmt3a associates with p63 to maintain high levels of DNA hydroxymethylation at the center of enhancers in a Tet2-dependent manner, whereas Dnmt3b promotes DNA methylation along the body of the enhancer. Depletion of either protein inactivates their target enhancers and profoundly affects epidermal stem cell function. Altogether, we reveal novel functions for Dnmt3a and Dnmt3b at enhancers that could contribute to their roles in disease and tumorigenesis.
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Affiliation(s)
- Lorenzo Rinaldi
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Doctor Aiguader 88, 08003 Barcelona, Spain.
| | - Debayan Datta
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
| | - Judit Serrat
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
| | - Lluis Morey
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Guiomar Solanas
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
| | - Alexandra Avgustinova
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
| | - Enrique Blanco
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Doctor Aiguader 88, 08003 Barcelona, Spain
| | - José Ignacio Pons
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
| | - David Matallanas
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland
| | - Alex Von Kriegsheim
- Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland
| | - Luciano Di Croce
- ICREA, Passeig de Lluís Companys 23, 08010 Barcelona, Spain; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Doctor Aiguader 88, 08003 Barcelona, Spain.
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; ICREA, Passeig de Lluís Companys 23, 08010 Barcelona, Spain.
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23
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Abstract
Mammalian embryonic development is a tightly regulated process that, from a single zygote, produces a large number of cell types with hugely divergent functions. Distinct cellular differentiation programmes are facilitated by tight transcriptional and epigenetic regulation. However, the contribution of epigenetic regulation to tissue homeostasis after the completion of development is less well understood. In this Review, we explore the effects of epigenetic dysregulation on adult stem cell function. We conclude that, depending on the tissue type and the epigenetic regulator affected, the consequences range from negligible to stem cell malfunction and disruption of tissue homeostasis, which may predispose to diseases such as cancer.
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24
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Aloia L, McKie MA, Huch M. Cellular plasticity in the adult liver and stomach. J Physiol 2016; 594:4815-25. [PMID: 27028579 DOI: 10.1113/jp271769] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 03/21/2016] [Indexed: 12/21/2022] Open
Abstract
Adult tissues maintain function and architecture through robust homeostatic mechanisms mediated by self-renewing cells capable of generating all resident cell types. However, severe injury can challenge the regeneration potential of such a stem/progenitor compartment. Indeed, upon injury adult tissues can exhibit massive cellular plasticity in order to achieve proper tissue regeneration, circumventing an impaired stem/progenitor compartment. Several examples of such plasticity have been reported in both rapidly and slowly self-renewing organs and follow conserved mechanisms. Upon loss of the cellular compartment responsible for maintaining homeostasis, quiescent or slowly proliferating stem/progenitor cells can acquire high proliferation potential and turn into active stem cells, or, alternatively, mature cells can de-differentiate into stem-like cells or re-enter the cell cycle to compensate for the tissue loss. This extensive cellular plasticity acts as a key mechanism to respond to multiple stimuli in a context-dependent manner, enabling tissue regeneration in a robust fashion. In this review cellular plasticity in the adult liver and stomach will be examined, highlighting the diverse cell populations capable of repairing the damaged tissue.
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Affiliation(s)
- Luigi Aloia
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Mikel Alexander McKie
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK
| | - Meritxell Huch
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK
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25
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The epigenetics of tumour initiation: cancer stem cells and their chromatin. Curr Opin Genet Dev 2016; 36:8-15. [PMID: 26874045 DOI: 10.1016/j.gde.2016.01.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/11/2016] [Accepted: 01/19/2016] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) have been identified in various tumours and are defined by their potential to initiate tumours upon transplantation, self-renew and reconstitute tumour heterogeneity. Modifications of the epigenome can favour tumour initiation by affecting genome integrity, DNA repair and tumour cell plasticity. Importantly, an in-depth understanding of the epigenomic alterations underlying neoplastic transformation may open new avenues for chromatin-targeted cancer treatment, as these epigenetic changes could be inherently more amenable to inhibition and reversal than hard-wired genomic alterations. Here we discuss how CSC function is affected by chromatin state and epigenomic instability.
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26
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Yang Q, Mas A, Diamond MP, Al-Hendy A. The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development. Reprod Sci 2016; 23:163-75. [PMID: 25922306 PMCID: PMC5933172 DOI: 10.1177/1933719115584449] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and ten-eleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17β-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.
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Affiliation(s)
- Qiwei Yang
- Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA
| | - Aymara Mas
- Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA
| | - Michael P Diamond
- Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA
| | - Ayman Al-Hendy
- Division of Translation Research, Department of Obstetrics and Gynecology, Georgia Regents University, Medical College of Georgia, Augusta, GA, USA
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Relton CL, Hartwig FP, Davey Smith G. From stem cells to the law courts: DNA methylation, the forensic epigenome and the possibility of a biosocial archive. Int J Epidemiol 2015; 44:1083-93. [PMID: 26424516 PMCID: PMC5279868 DOI: 10.1093/ije/dyv198] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The growth in epigenetics continues to attract considerable cross-disciplinary interest, apparently representing an opportunity to move beyond genomics towards the goal of understanding phenotypic variability from molecular through organismal to the societal level. The epigenome may also harbour useful information about life-time exposures (measured or unmeasured) irrespective of their influence on health or disease, creating the potential for a person-specific biosocial archive . Furthermore such data may prove of use in providing identifying information, providing the possibility of a future forensic epigenome . The mechanisms involved in ensuring that environmentally induced epigenetic changes perpetuate across the life course remain unclear. Here we propose a potential role of adult stem cells in maintaining epigenetic states provides a useful basis for formulating such epidemiologically-relevant concepts.
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Affiliation(s)
- Caroline L Relton
- MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK
| | | | - George Davey Smith
- MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, UK
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Muñoz-Cánoves P, Di Croce L. Special issue: epigenetics: introduction. FEBS J 2015; 282:1569-70. [PMID: 25828932 DOI: 10.1111/febs.13281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/25/2015] [Indexed: 12/17/2022]
Abstract
Epigenetic studies focus on changes in genetic information that rely on histone modification, which complements information encoded by the DNA sequence. Research in this rapidly expanding field has greatly contributed to a better understanding of processes such as gene regulation, chromatin structure, and cell differentiation and disease. The most recent advances in this area are reviewed in the collection of papers included in this Special Issue.
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Affiliation(s)
- Pura Muñoz-Cánoves
- Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative Diseases, Barcelona, Spain; Institucio Catalana de Recerca i Estudis Avancçats, Barcelona, Spain.
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