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Affiliation(s)
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Cited by Other Article(s) |
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1
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Didriksen BJ, Eshleman EM, Alenghat T. Epithelial regulation of microbiota-immune cell dynamics. Mucosal Immunol 2024; 17:303-313. [PMID: 38428738 PMCID: PMC11412483 DOI: 10.1016/j.mucimm.2024.02.008] [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: 12/12/2023] [Revised: 02/09/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024]
Abstract
The mammalian gastrointestinal tract hosts a diverse community of trillions of microorganisms, collectively termed the microbiota, which play a fundamental role in regulating tissue physiology and immunity. Recent studies have sought to dissect the cellular and molecular mechanisms mediating communication between the microbiota and host immune system. Epithelial cells line the intestine and form an initial barrier separating the microbiota from underlying immune cells, and disruption of epithelial function has been associated with various conditions ranging from infection to inflammatory bowel diseases and cancer. From several studies, it is now clear that epithelial cells integrate signals from commensal microbes. Importantly, these non-hematopoietic cells also direct regulatory mechanisms that instruct the recruitment and function of microbiota-sensitive immune cells. In this review, we discuss the central role that has emerged for epithelial cells in orchestrating intestinal immunity and highlight epithelial pathways through which the microbiota can calibrate tissue-intrinsic immune responses.
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Affiliation(s)
- Bailey J Didriksen
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Emily M Eshleman
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
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2
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Lu H, Yan H, Li X, Xing Y, Ye Y, Jiang S, Ma L, Ping J, Zuo H, Hao Y, Yu C, Li Y, Zhou G, Lu Y. Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury. Commun Biol 2023; 6:1248. [PMID: 38071238 PMCID: PMC10710489 DOI: 10.1038/s42003-023-05645-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Intestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for pelvic, abdominal, and retroperitoneal tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration. We showed that the various cell types of intestine exhibited heterogeneous radiosensitivities. We revealed the distinct dynamic patterns of three subtypes of intestinal stem cells (ISCs), and the cellular trajectory analysis suggested a complex interconversion pattern among them. For the immune cells, we found that Ly6c+ monocytes can give rise to both pro-inflammatory macrophages and resident macrophages after RIII. Through cellular communication analysis, we identified a positive feedback loop between the macrophages and endothelial cells, which could amplify the inflammatory response induced by radiation. Besides, we identified different T cell subtypes and revealed their role in immunomodulation during the early stage of RIII through inflammation and defense response relevant signaling pathways. Overall, our study provides a valuable single-cell map of the multicellular dynamics during RIII and regeneration, which may facilitate the understanding of the mechanism of RIII.
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Affiliation(s)
- Hao Lu
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hua Yan
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Xiaoyu Li
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yuan Xing
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yumeng Ye
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Siao Jiang
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
- College of Life Sciences, Hebei University, Baoding City, Hebei Province, 071002, China
| | - Luyu Ma
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Jie Ping
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Hongyan Zuo
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yanhui Hao
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chao Yu
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Yang Li
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- Academy of Life Sciences, Anhui Medical University, Hefei City, Anhui Province, 230032, China.
| | - Gangqiao Zhou
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, Jiangsu Province, 211166, China.
| | - Yiming Lu
- Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- College of Life Sciences, Hebei University, Baoding City, Hebei Province, 071002, China.
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3
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Naderinezhad S, Zhang G, Wang Z, Zheng D, Hulsurkar M, Bakhoum M, Su N, Yang H, Shen T, Li W. A novel GRK3-HDAC2 regulatory pathway is a key direct link between neuroendocrine differentiation and angiogenesis in prostate cancer progression. Cancer Lett 2023; 571:216333. [PMID: 37543278 PMCID: PMC11235056 DOI: 10.1016/j.canlet.2023.216333] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/24/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical promoter for both phenotypes too. Of note, GRK3 phosphorylates HDAC2 at S394, which enhances HDAC2's epigenetic repression of potent anti-angiogenic factor Thrombospondin 1 (TSP1) and master NE-repressor RE1 Silencing Transcription Factor (REST). Intriguingly, REST suppresses angiogenesis while TSP1 suppresses NE marker expression in PCa cells, indicative of their novel functions and their synergy in cross-repressing the two phenotypes. Furthermore, the GRK3-HDAC2 pathway is activated by androgen deprivation therapy and hypoxia, both known to promote NED and angiogenesis in PCa. These results indicate that NED and angiogenesis converge on GRK3-enhanced HDAC2 suppression of REST and TSP1, which constitutes a key missing link between two prominent phenotypes of NEPC.
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Affiliation(s)
- Samira Naderinezhad
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Guoliang Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zheng Wang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Dayong Zheng
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Mohit Hulsurkar
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Michael Bakhoum
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ning Su
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Han Yang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Tao Shen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Wenliang Li
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
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4
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Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne) 2023; 14:1169624. [PMID: 37560311 PMCID: PMC10407565 DOI: 10.3389/fendo.2023.1169624] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Affiliation(s)
| | - Van B. Lu
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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5
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Dothel G, Barbaro MR, Di Vito A, Ravegnini G, Gorini F, Monesmith S, Coschina E, Benuzzi E, Fuschi D, Palombo M, Bonomini F, Morroni F, Hrelia P, Barbara G, Angelini S. New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics. J Gastroenterol 2023; 58:605-621. [PMID: 37160449 PMCID: PMC10307698 DOI: 10.1007/s00535-023-01997-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/19/2023] [Indexed: 05/11/2023]
Abstract
Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology.
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Affiliation(s)
- Giovanni Dothel
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Connect By Circular Lab SRL, Madrid, Spain
| | | | - Aldo Di Vito
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Francesca Gorini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Sarah Monesmith
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Emma Coschina
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Eva Benuzzi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Daniele Fuschi
- IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Marta Palombo
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Francesca Bonomini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Fabiana Morroni
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
- Inter-Departmental Center for Health Sciences & Technologies, CIRI-SDV, University of Bologna, Bologna, Italy
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6
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Lozenov S, Krastev B, Nikolaev G, Peshevska-Sekulovska M, Peruhova M, Velikova T. Gut Microbiome Composition and Its Metabolites Are a Key Regulating Factor for Malignant Transformation, Metastasis and Antitumor Immunity. Int J Mol Sci 2023; 24:5978. [PMID: 36983053 PMCID: PMC10054493 DOI: 10.3390/ijms24065978] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
The genetic and metabolomic abundance of the microbiome exemplifies that the microbiome comprises a more extensive set of genes than the entire human genome, which justifies the numerous metabolic and immunological interactions between the gut microbiota, macroorganisms and immune processes. These interactions have local and systemic impacts that can influence the pathological process of carcinogenesis. The latter can be promoted, enhanced or inhibited by the interactions between the microbiota and the host. This review aimed to present evidence that interactions between the host and the gut microbiota might be a significant exogenic factor for cancer predisposition. It is beyond doubt that the cross-talk between microbiota and the host cells in terms of epigenetic modifications can regulate gene expression patterns and influence cell fate in both beneficial and adverse directions for the host's health. Furthermore, bacterial metabolites could shift pro- and anti-tumor processes in one direction or another. However, the exact mechanisms behind these interactions are elusive and require large-scale omics studies to better understand and possibly discover new therapeutic approaches for cancer.
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Affiliation(s)
- Stefan Lozenov
- Laboratory for Control and Monitoring of the Antibiotic Resistance, National Centre for Infectious and Parasitic Diseases, 26 Yanko Sakazov Blvd, 1504 Sofia, Bulgaria;
| | - Boris Krastev
- Nadezhda Paradise Medical Center, 1330 Sofia, Bulgaria;
| | - Georgi Nikolaev
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1504 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Department of Gastroenterology, University Hospital Lozenetz, Sofia, Medical Faculty, Sofia University “St. Kliment Ohridski”, 1407 Sofia, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, 5804 Pleven, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Kozyak 1 str., 1407 Sofia, Bulgaria
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7
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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8
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Abstract
The gastrointestinal tract is continuously exposed to trillions of commensal microbes, collectively termed the microbiota, which are environmental stimuli that can direct health and disease within the host. In addition to well-established bacterial sensing pathways, microbial signals are also integrated through epigenetic modifications that calibrate the transcriptional program of host cells without altering the underlying genetic code. Microbiota-sensitive epigenetic changes include modifications to the DNA or histones, as well as regulation of non-coding RNAs. While microbiota-sensitive epigenetic mechanisms have been described in both local intestinal cells and as well in peripheral tissues, further research is required to fully decipher the complex relationship between the host and microbiota. This Review highlights current understandings of epigenetic regulation by gut microbiota and important implications of these findings in guiding therapeutic approaches to prevent or combat diseases driven by impaired microbiota-host interactions.
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Affiliation(s)
- Vivienne Woo
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA,CONTACT Theresa Alenghat Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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9
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Eshleman EM, Alenghat T. Epithelial sensing of microbiota-derived signals. Genes Immun 2021; 22:237-246. [PMID: 33824498 PMCID: PMC8492766 DOI: 10.1038/s41435-021-00124-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 02/01/2023]
Abstract
The gastrointestinal tract harbors trillions of microbial species, collectively termed the microbiota, which establish a symbiotic relationship with the host. Decades of research have emphasized the necessity of microbial signals in the development, maturation, and function of host physiology. However, changes in the composition or containment of the microbiota have been linked to the development of several chronic inflammatory diseases, including inflammatory bowel diseases. Intestinal epithelial cells (IECs) are in constant contact with the microbiota and are critical for maintaining intestinal homeostasis. Signals from the microbiota are directly sensed by IECs and influence intestinal health by calibrating immune cell responses and fortifying intestinal barrier function. IECs detect commensal microbes through engagement of common pattern recognition receptors or by sensing the production of microbial-derived metabolites. Deficiencies in these microbial-detecting pathways in IECs leads to impaired epithelial barrier function and altered intestinal homeostasis. This Review aims to highlight the pathways by which IECs sense microbiota-derived signals and the necessity of these detection pathways in maintaining epithelial barrier integrity.
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Affiliation(s)
- Emily M Eshleman
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Theresa Alenghat
- Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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10
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Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct Target Ther 2021; 6:245. [PMID: 34176928 PMCID: PMC8236488 DOI: 10.1038/s41392-021-00646-9] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 05/09/2021] [Accepted: 05/13/2021] [Indexed: 02/05/2023] Open
Abstract
Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.
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11
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Gonneaud A, Turgeon N, Boisvert FM, Boudreau F, Asselin C. JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in Hdac1- and Hdac2-Intestinal Epithelial Cell-Deficient Mice. Cells 2021; 10:224. [PMID: 33498747 PMCID: PMC7911100 DOI: 10.3390/cells10020224] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
We have previously reported that histone deacetylase epigenetic regulator Hdac1 and Hdac2 deletion in intestinal epithelial cells (IEC) disrupts mucosal tissue architecture and barrier, causing chronic inflammation. In this study, proteome and transcriptome analysis revealed the importance of signaling pathways induced upon genetic IEC-Hdac1 and Hdac2 deletion. Indeed, Gene Ontology biological process analysis of enriched deficient IEC RNA and proteins identified common pathways, including lipid metabolic and oxidation-reduction process, cell adhesion, and antigen processing and presentation, related to immune responses, correlating with dysregulation of major histocompatibility complex (MHC) class II genes. Top upstream regulators included regulators associated with environmental sensing pathways to xenobiotics, microbial and diet-derived ligands, and endogenous metabolites. Proteome analysis revealed mTOR signaling IEC-specific defects. In addition to mTOR, the STAT and Notch pathways were dysregulated specifically in jejunal IEC. To determine the impact of pathway dysregulation on mutant jejunum alterations, we treated mutant mice with Tofacitinib, a JAK inhibitor. Treatment with the inhibitor partially corrected proliferation and tight junction defects, as well as niche stabilization by increasing Paneth cell numbers. Thus, IEC-specific histone deacetylases 1 (HDAC1) and 2 (HDAC2) support intestinal homeostasis by regulating survival and translation processes, as well as differentiation and metabolic pathways. HDAC1 and HDAC2 may play an important role in the regulation of IEC-specific inflammatory responses by controlling, directly or indirectly, the JAK/STAT pathway. IEC-specific JAK/STAT pathway deregulation may be, at least in part, responsible for intestinal homeostasis disruption in mutant mice.
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Affiliation(s)
- Alexis Gonneaud
- Département D’immunologie et Biologie Cellulaire, Pavillon de Recherche Appliquée Sur le Cancer, Faculté de Médecine et Des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada; (N.T.); (F.-M.B.); (F.B.); (C.A.)
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12
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Transcriptional programmes underlying cellular identity and microbial responsiveness in the intestinal epithelium. Nat Rev Gastroenterol Hepatol 2021; 18:7-23. [PMID: 33024279 PMCID: PMC7997278 DOI: 10.1038/s41575-020-00357-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/12/2020] [Indexed: 12/19/2022]
Abstract
The intestinal epithelium serves the unique and critical function of harvesting dietary nutrients, while simultaneously acting as a cellular barrier separating tissues from the luminal environment and gut microbial ecosystem. Two salient features of the intestinal epithelium enable it to perform these complex functions. First, cells within the intestinal epithelium achieve a wide range of specialized identities, including different cell types and distinct anterior-posterior patterning along the intestine. Second, intestinal epithelial cells are sensitive and responsive to the dynamic milieu of dietary nutrients, xenobiotics and microorganisms encountered in the intestinal luminal environment. These diverse identities and responsiveness of intestinal epithelial cells are achieved in part through the differential transcription of genes encoded in their shared genome. Here, we review insights from mice and other vertebrate models into the transcriptional regulatory mechanisms underlying intestinal epithelial identity and microbial responsiveness, including DNA methylation, chromatin accessibility, histone modifications and transcription factors. These studies are revealing that most transcription factors involved in intestinal epithelial identity also respond to changes in the microbiota, raising both opportunities and challenges to discern the underlying integrative transcriptional regulatory networks.
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13
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Rispal J, Escaffit F, Trouche D. Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity. Stem Cell Rev Rep 2020; 16:1062-1080. [PMID: 33051755 PMCID: PMC7667136 DOI: 10.1007/s12015-020-10055-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
The rapid renewal of intestinal epithelium is mediated by a pool of stem cells, located at the bottom of crypts, giving rise to highly proliferative progenitor cells, which in turn differentiate during their migration along the villus. The equilibrium between renewal and differentiation is critical for establishment and maintenance of tissue homeostasis, and is regulated by signaling pathways (Wnt, Notch, Bmp…) and specific transcription factors (TCF4, CDX2…). Such regulation controls intestinal cell identities by modulating the cellular transcriptome. Recently, chromatin modification and dynamics have been identified as major actors linking signaling pathways and transcriptional regulation in the control of intestinal homeostasis. In this review, we synthesize the many facets of chromatin dynamics involved in controlling intestinal cell fate, such as stemness maintenance, progenitor identity, lineage choice and commitment, and terminal differentiation. In addition, we present recent data underlying the fundamental role of chromatin dynamics in intestinal cell plasticity. Indeed, this plasticity, which includes dedifferentiation processes or the response to environmental cues (like microbiota’s presence or food ingestion), is central for the organ’s physiology. Finally, we discuss the role of chromatin dynamics in the appearance and treatment of diseases caused by deficiencies in the aforementioned mechanisms, such as gastrointestinal cancer, inflammatory bowel disease or irritable bowel syndrome.
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Graphical abstract
- Jérémie Rispal
- LBCMCP, Centre of Integrative Biology (CBI), Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
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- Fabrice Escaffit
- LBCMCP, Centre of Integrative Biology (CBI), Université de Toulouse, CNRS, UPS, Toulouse, 31062, France.
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- Didier Trouche
- LBCMCP, Centre of Integrative Biology (CBI), Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
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14
Maucort C, Di Giorgio A, Azoulay S, Duca M. Differentiation of Cancer Stem Cells by Using Synthetic Small Molecules: Toward New Therapeutic Strategies against Therapy Resistance.
ChemMedChem 2020;
16:14-29. [PMID:
32803855 DOI:
10.1002/cmdc.202000251]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/19/2020] [Indexed: 12/12/2022]
Abstract
Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.
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Affiliation(s)
- Chloé Maucort
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
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- Audrey Di Giorgio
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
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- Stéphane Azoulay
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
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- Maria Duca
- Université Côte d'Azur, CNRS, Institute of Chemistry of Nice (ICN), 28 avenue Valrose, 06108, Nice, France
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15
Baulies A, Angelis N, Li VSW. Hallmarks of intestinal stem cells.
Development 2020;
147:147/15/dev182675. [PMID:
32747330 DOI:
10.1242/dev.182675]
[Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Intestinal stem cells (ISCs) are highly proliferative cells that fuel the continuous renewal of the intestinal epithelium. Understanding their regulatory mechanisms during tissue homeostasis is key to delineating their roles in development and regeneration, as well as diseases such as bowel cancer and inflammatory bowel disease. Previous studies of ISCs focused mainly on the position of these cells along the intestinal crypt and their capacity for multipotency. However, evidence increasingly suggests that ISCs also exist in distinct cellular states, which can be an acquired rather than a hardwired intrinsic property. In this Review, we summarise the recent findings into how ISC identity can be defined by proliferation state, signalling crosstalk, epigenetics and metabolism, and propose an update on the hallmarks of ISCs. We further discuss how these properties contribute to intestinal development and the dynamics of injury-induced regeneration.
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Affiliation(s)
- Anna Baulies
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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- Nikolaos Angelis
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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- Vivian S W Li
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
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16
Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer.
Biomedicines 2020;
8:biomedicines8020022. [PMID:
32019149 PMCID:
PMC7168248 DOI:
10.3390/biomedicines8020022]
[Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Accepted: 01/27/2020] [Indexed: 12/12/2022] Open
Abstract
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
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17
Cheng CW, Biton M, Haber AL, Gunduz N, Eng G, Gaynor LT, Tripathi S, Calibasi-Kocal G, Rickelt S, Butty VL, Moreno-Serrano M, Iqbal AM, Bauer-Rowe KE, Imada S, Ulutas MS, Mylonas C, Whary MT, Levine SS, Basbinar Y, Hynes RO, Mino-Kenudson M, Deshpande V, Boyer LA, Fox JG, Terranova C, Rai K, Piwnica-Worms H, Mihaylova MM, Regev A, Yilmaz ÖH. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.
Cell 2019;
178:1115-1131.e15. [PMID:
31442404 PMCID:
PMC6732196 DOI:
10.1016/j.cell.2019.07.048]
[Citation(s) in RCA: 259] [Impact Index Per Article: 43.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 06/03/2019] [Accepted: 07/25/2019] [Indexed: 01/18/2023]
Abstract
Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
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Affiliation(s)
- Chia-Wei Cheng
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
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- Moshe Biton
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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- Adam L Haber
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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- Nuray Gunduz
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, 06800 Ankara, Turkey
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- George Eng
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA
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- Liam T Gaynor
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
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- Surya Tripathi
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
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- Gizem Calibasi-Kocal
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey
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- Steffen Rickelt
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
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- Vincent L Butty
- BioMicro Center at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA
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- Ameena M Iqbal
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
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- Shinya Imada
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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- Mehmet Sefa Ulutas
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, Siirt University, Science and Arts Faculty, 56100 Siirt, Turkey
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- Mark T Whary
- Division of Comparative Medicine, Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
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- Stuart S Levine
- BioMicro Center at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA
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- Yasemin Basbinar
- Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey
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- Richard O Hynes
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA
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- Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA
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- Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA
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- James G Fox
- Division of Comparative Medicine, Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
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- Christopher Terranova
- Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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- Kunal Rai
- Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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- Helen Piwnica-Worms
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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- Maria M Mihaylova
- Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210 USA
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- Aviv Regev
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA
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- Ömer H Yilmaz
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
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18
Du W, Wang N, Li F, Jia K, An J, Liu Y, Wang Y, Zhu L, Zhao S, Hao J. STAT3 phosphorylation mediates high glucose-impaired cell autophagy in an HDAC1-dependent and -independent manner in Schwann cells of diabetic peripheral neuropathy.
FASEB J 2019;
33:8008-8021. [PMID:
30913399 DOI:
10.1096/fj.201900127r]
[Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Schwann cells are the main supportive cells of the peripheral nerves. Schwann cells suffer inhibition of autophagy under hyperglycemia treatment in diabetic peripheral neuropathy (DPN). However, the exact mechanism is still not fully elucidated. We first observed the decrease of autophagy markers (LC3-II/LC3-I, P62) in the sciatic nerves of diabetic mice vs. normal mice, accompanied with the loss of myelinated nerve fibers and abnormal myelin sheath. In line with this, LC3-II/LC3-I and P62 were also significantly reduced in high glucose-treated rat Schwann cell 96 (RSC96) cells compared with normal glucose-treated cells. Furthermore, we found that trichostatin A [an inhibitor of histone deacetylase (HDAC)] evidently improved LC3-II/LC3-I in high glucose-treated RSC96 cells, without an effect on P62 expression. Again, HDAC1 and HDAC5 were revealed to be increased in RSC96 cells stimulated with high glucose. Inhibition of HDAC1 but not HDAC5 by small hairpin RNA vector enhanced LC3-II/LC3-I in high glucose-cultured RSC96 cells. In addition, LC3-II conversion regulators [autophagy-related protein (Atg)3, Atg5, and Atg7] were detected in high glucose-treated and HDAC1-knockdown RSC96 cells, and Atg3 was proven to be the key target of HDAC1. The presuppression of Atg3 offset the improvement of LC3-II/LC3-I resulting from HDAC1 inhibition in high glucose-treated RSC96 cells. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway was activated in RSC96 cells treated with high glucose, which was indicated by increased STAT3 phosphorylation. Blocking STAT3 phosphorylation by chemical inhibitor AG490 induced HDAC1 down-regulation followed by increases in Atg3 and LC3-II/LC3-I. Interestingly, we also found that AG490 treatment enhanced P62 expression in high glucose-stimulated RSC96 cells. Taken together, our findings demonstrate that hyperglycemia inhibits LC3-II/LC3-I in an HDAC1-Atg3-dependent manner and decreases P62 expression in an HDAC-independent manner via the JAK-STAT3 signaling pathway in the Schwann cells of DPN.-Du, W., Wang, N., Li, F. Jia, K., An, J., Liu, Y., Wang, Y., Zhu, L., Zhao, S. Hao, J. STAT3 phosphorylation mediates high glucose-impaired cell autophagy in an HDAC1-dependent and -independent manner in Schwann cells of diabetic peripheral neuropathy.
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Affiliation(s)
- Wei Du
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Na Wang
- Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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- Fan Li
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Keqi Jia
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Jiahui An
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Yaping Liu
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Yuxue Wang
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Lin Zhu
- Department of Electromyogram, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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- Song Zhao
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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- Jun Hao
- Department of Pathology, Hebei Medical University, Shijiazhuang, China
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19
Implication for Cancer Stem Cells in Solid Cancer Chemo-Resistance: Promising Therapeutic Strategies Based on the Use of HDAC Inhibitors.
J Clin Med 2019;
8:jcm8070912. [PMID:
31247937 PMCID:
PMC6678716 DOI:
10.3390/jcm8070912]
[Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 12/20/2022] Open
Abstract
Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage differentiation potential, are known to be intrinsically resistant to anticancer treatments. In this review, we analyzed the implications for CSCs in drug resistance and described that multiple alterations in morphogenetic pathways (i.e., Hippo, Wnt, JAK/STAT, TGF-β, Notch, Hedgehog pathways) were suggested to be critical for CSC plasticity. By interrogating The Cancer Genome Atlas (TCGA) datasets, we first analyzed the prevalence of morphogenetic pathways alterations in solid tumors with associated outcomes. Then, by highlighting epigenetic relevance in CSC development and maintenance, we selected histone deacetylase inhibitors (HDACi) as potential agents of interest to target this subpopulation based on the pleiotropic effects exerted specifically on altered morphogenetic pathways. In detail, we highlighted the role of HDACi in solid cancers and, specifically, in the CSC subpopulation and we pointed out some mechanisms by which HDACi are able to overcome drug resistance and to modulate stemness. Although, further clinical and preclinical investigations should be conducted to disclose the unclear mechanisms by which HDACi modulate several signaling pathways in different tumors. To date, several lines of evidence support the testing of novel combinatorial therapeutic strategies based on the combination of drugs commonly used in clinical practice and HDACi to improve therapeutic efficacy in solid cancer patients.
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20
Yuan L, Liu C, Wan Y, Yan H, Li T. Effect of HDAC2/Inpp5f on neuropathic pain and cognitive function through regulating PI3K/Akt/GSK-3β signal pathway in rats with neuropathic pain.
Exp Ther Med 2019;
18:678-684. [PMID:
31281447 PMCID:
PMC6580097 DOI:
10.3892/etm.2019.7622]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
The effect of histone deacetylase (HDAC)2/Inositol polyphosphate-5-phosphatase F (Inpp5f) on neuropathic pain and cognitive dysfunction through regulating PI3K/Akt/GSK-3β signal pathway in rats with neuropathic pain was investigated. A total of 80 SPF mature male SD rats were averagely randomized into the sham operation group, the model group, the HDAC2 intervention group (group A) and the Inpp5f intervention group (group B). The rat models of neuropathic pain were established in the model group, and groups A and B. At the 15th day after modeling, rats in group A were transfected with the interference vector of HDAC2, and rats in group B were transfected with the overexpression vector of Inpp5f. Rats in the four groups were observed before modeling, after modeling/before intervention and 3 days after intervention in terms of paw thermal withdrawal latency (PWL), paw withdrawal mechanical threshold (PWT) and changes in cognitive function (Morris water maze and passive avoidance task). Then the rats were sacrificed. RT-qPCR and western blot analysis were used to detect the levels of HDAC2 mRNA, Inpp5f mRNA, phosphorylated PI3K (p-PI3K), phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β) in rat brain tissue. Correlation of HDAC2 mRNA with Inpp5f mRNA expression levels was detected by Pearsons correlation analysis. Compared with the sham operation group, PWL was significantly lower while PWT was higher in the other 3 groups (P<0.05). Three days after intervention, PWL was significantly higher while PWT was significantly lower (P<0.05). Inhibiting the expression of HDAC2 or promoting the expression of Inpp5f can effectively improve cognitive function in rats (P<0.05). After intervention, compared with the sham operation group, rats in the other 3 groups had higher HDAC2 mRNA level and lower Inpp5f mRNA level (P<0.05). In conclusion, neuropathic pain can cause an increase in HDAC2 expression level and a decrease in Inpp5f expression level, and activate the PI3K/Akt/GSK-3β signal pathway. Inhibition of HDAC2 expression can inhibit the activation of PI3K/Akt/GSK-3β signal pathway through increasing Inpp5f expression, thus improving the condition and cognitive disorder of rats with neuropathic pain.
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Affiliation(s)
- Lili Yuan
- Department of Anesthesiology, Fifth Hospital in Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430050, P.R. China
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- Caihua Liu
- Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430050, P.R. China
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- Yingchun Wan
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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- Hong Yan
- Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430050, P.R. China
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- Tao Li
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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21
Ma S, Liu T, Xu L, Wang Y, Zhou J, Huang T, Li P, Liu H, Zhang Y, Zhou X, Cui Y, Zang X, Wang Y, Guan F. Histone deacetylases inhibitor MS-275 suppresses human esophageal squamous cell carcinoma cell growth and progression via the PI3K/Akt/mTOR pathway.
J Cell Physiol 2019;
234:22400-22410. [PMID:
31120582 DOI:
10.1002/jcp.28805]
[Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 12/18/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with low survival rate, so new therapies are urgently needed. Histone deacetylases (HDACs) play a critical role in tumorigenesis, and HDACs inhibition is a potential therapeutic target in ESSC. In our study, we evaluated the effect and molecular mechanism of MS-275 (an inhibitor of HDACs) on ESCC cells. We found that HDAC1 and HDAC2 were overexpressed in ESCC tissues and related with clinical pathological features of patients with ESCC. MS-275 markedly reduced HDAC1 and HDAC2 expression, whereas increased the level of AcH3 and AcH2B. MS-275 suppressed proliferation and clonogenicity of ESCC cells in a concentration-dependent manner. In addition, MS-275 induced apoptosis, arrested cell cycle, and inhibited migration, epithelial-mesenchymal transition, and sphere-forming ability of ESCC cells in vitro. Moreover, p-Akt1 and p-mTOR were downregulated by MS-275. Finally, MS-275 significantly inhibited tumor growth in vivo. Taken together, HDAC1 and HDAC2 are associated with the progression of ESCC, and MS-275 hinders the progression and stemness of ESCC cells by suppressing the PI3K/Akt/mTOR pathway. Our findings show that MS-275 inhibits ESCC cells growth in vitro and in vivo, which is a potential drug for the ESCC therapy.
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Affiliation(s)
- Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Tengfei Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Ling Xu
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Department of Anesthesiology, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
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- Yaping Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Jiankang Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Tuanjie Huang
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Peng Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Clinical Laboratory, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian, Henan, China
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- Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Xinkui Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Yuanbo Cui
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
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- Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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- Yuming Wang
- Henan University People's Hospital, Zhengzhou, Henan, China
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- Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Henan Provincial People's Hospital, Zhengzhou, Henan, China
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22
Martinez-Redondo P, Izpisua Belmonte JC. Tailored chromatin modulation to promote tissue regeneration.
Semin Cell Dev Biol 2019;
97:3-15. [PMID:
31028854 DOI:
10.1016/j.semcdb.2019.04.015]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 04/22/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
Epigenetic regulation of gene expression is fundamental in the maintenance of cellular identity and the regulation of cellular plasticity during tissue repair. In fact, epigenetic modulation is associated with the processes of cellular de-differentiation, proliferation, and re-differentiation that takes place during tissue regeneration. In here we explore the epigenetic events that coordinate tissue repair in lower vertebrates with high regenerative capacity, and in mammalian adult stem cells, which are responsible for the homeostasis maintenance of most of our tissues. Finally we summarize promising CRISPR-based editing technologies developed during the last years, which look as promising tools to not only study but also promote specific events during tissue regeneration.
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Affiliation(s)
- Paloma Martinez-Redondo
- Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United States
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- Juan Carlos Izpisua Belmonte
- Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, United States.
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23
HDAC1 and HDAC2 independently regulate common and specific intrinsic responses in murine enteroids.
Sci Rep 2019;
9:5363. [PMID:
30926862 PMCID:
PMC6441098 DOI:
10.1038/s41598-019-41842-6]
[Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/19/2019] [Indexed: 02/07/2023] Open
Abstract
Both HDAC1 and HDAC2 are class I deacetylases acting as erasers of lysine-acetyl marks on histones and non-histone proteins. Several histone deacetylase inhibitors, either endogenous to the cell, such as the ketogenic β-hydroxybutyrate metabolite, or exogenous, such as butyrate, a microbial-derived metabolite, regulate HDAC activity. Different combinations of intestinal epithelial cell (IEC)-specific Hdac1 and/or Hdac2 deletion differentially alter mucosal homeostasis in mice. Thus, HDAC1 and HDAC2 could act as sensors and transmitters of environmental signals to the mucosa. In this study, enteroid culture models deleted for Hdac1 or Hdac2 were established to determine IEC-specific function as assessed by global transcriptomic and proteomic approaches. Results show that Hdac1 or Hdac2 deficiency altered differentiation of Paneth and goblet secretory cells, which sustain physical and chemical protection barriers, and increased intermediate secretory cell precursor numbers. Furthermore, IEC Hdac1- and Hdac2-dependent common and specific biological processes were identified, including oxidation-reduction, inflammatory responses, and lipid-related metabolic processes, as well as canonical pathways and upstream regulators related to environment-dependent signaling through steroid receptor pathways, among others. These findings uncover unrecognized regulatory similarities and differences between Hdac1 and Hdac2 in IEC, and demonstrate how HDAC1 and HDAC2 may complement each other to regulate the intrinsic IEC phenotype.
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24
HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases.
Int J Mol Sci 2019;
20:ijms20061329. [PMID:
30884785 PMCID:
PMC6471162 DOI:
10.3390/ijms20061329]
[Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/05/2019] [Accepted: 03/12/2019] [Indexed: 02/07/2023] Open
Abstract
Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.
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25
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal tract. The incidence of IBD is increasing, with more cases occurring in developed countries. Multiple factors such as genetics, environmental changes, gut microbiota, and immune abnormalities have been associated with development of IBD. In recent years, it has become increasingly apparent that epigenetic modifications of chromatin and the manner in which chromatin is organized in the nucleus are additionally important elements that can influence responses induced by the factors described above, and may therefore contribute to the onset and pathogenesis of IBD. Epigenetics and chromatin organization regulate diverse functions that include maintenance of homeostasis in the intestinal epithelium, the development and differentiation of immune cells, and modulation of responses generated by the immune system to defend against potential pathogens. Furthermore, changes in epigenetic chromatin marks and in chromatin organization have now been linked to differential gene expression in IBD patient cells. Although direct evidence for a role of histone modifications in IBD is currently very limited, in this review, we summarize the links between various epigenetic modifications, the proteins that catalyze or recognize these modifications, and the development or progression of IBD in human and experimental IBD. We also discuss how epigenetics influence the organization of DNA contacts to regulate gene expression and the implications this may have for diagnosing and treating IBD.
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Affiliation(s)
- Greeshma Ray
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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- Michelle S Longworth
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA,Address correspondence to: Michelle S. Longworth, 9500 Euclid Ave NC22, Cleveland, OH 44195 ()
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26
Prasetyanti PR, van Hooff SR, van Herwaarden T, de Vries N, Kalloe K, Rodermond H, van Leersum R, de Jong JH, Franitza M, Nürnberg P, Todaro M, Stassi G, Medema JP. Capturing colorectal cancer inter-tumor heterogeneity in patient-derived xenograft (PDX) models.
Int J Cancer 2018;
144:366-371. [PMID:
30151914 PMCID:
PMC6587871 DOI:
10.1002/ijc.31767]
[Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/11/2018] [Accepted: 07/09/2018] [Indexed: 01/11/2023]
Abstract
Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, to provide a robust preclinical platform, PDXs need to accommodate the tumor heterogeneity that is observed in patients. Colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features. Surprisingly, using a set of CRC patients, we revealed the partial representation of tumor heterogeneity in PDX models. The epithelial subtypes, the largest subgroups of CRC subtype, were very ineffective in establishing PDXs, indicating the need for further optimization to develop an effective personalized therapeutic approach to CRC. Moreover, we showed that tumor cell proliferation was associated with successful PDX establishment and able to distinguish patient with poor clinical outcomes within CMS2 group.
What's new?
Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features, and to what extent the existing CRC PDX collection represents the inter‐patient heterogeneity remains an open question. This study identifies a subtype‐specific bias in the establishment of PDXs from CRC patients, leaving the major subtype CMS2 strongly underrepresented. Additionally, the findings suggest that further classification within CMS can be achieved. For CMS2, the proliferation‐related marker Ki67 may thus help refine patient classification, estimate prognosis, and guide treatment decisions.
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Affiliation(s)
- Pramudita R Prasetyanti
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Tessa van Herwaarden
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Nathalie de Vries
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Kieshen Kalloe
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Hans Rodermond
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Ronald van Leersum
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Joan H de Jong
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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- Marek Franitza
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
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- Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
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- Giorgio Stassi
- Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
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- Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
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27
ZBP-89 function in colonic stem cells and during butyrate-induced senescence.
Oncotarget 2017;
8:94330-94344. [PMID:
29212231 PMCID:
PMC5706877 DOI:
10.18632/oncotarget.21698]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/08/2017] [Indexed: 01/29/2023] Open
Abstract
ZBP-89 (Zfp148, ZNF148) is a Kruppel-type zinc-finger family transcription factor that binds to GC-rich DNA elements. Earlier studies in cell lines demonstrated that ZBP-89 cooperates with Wnt β-catenin signaling by inducing β-catenin gene expression. Since β-catenin levels are normally highest at the crypt base, we examined whether ZBP-89 is required for stem cell maintenance. Lineage-tracing using a Zfp148CreERT2 transgenic line demonstrated expression in both intestine and colonic stem cells. Deleting the Zfp148 locus in the colon using the Cdx2NLSCreERT2 transgene, reduced the size and number of polyps formed in the Apc-deleted mice. Since colon polyps form in the presence of butyrate, a short chain fatty acid that suppresses cell growth, we examined the direct effect of butyrate on colon organoid survival. Butyrate induced senescence of colon organoids carrying the Apc deletion, only when Zfp148 was deleted. Using quantitative PCR and chromatin immunoprecipitation, we determined that butyrate treatment of colon cell lines suppressed ZNF148 gene expression, inducing CDKN2a (p16Ink4a ) gene expression. Collectively, Zfp148 mRNA is expressed in CBCs, and is required for stem cell maintenance and colonic transformation. Butyrate induces colonic cell senescence in part through suppression of ZBP-89 gene expression and its subsequent occupancy of the CDKN2A promoter.
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28
Milstone ZJ, Lawson G, Trivedi CM. Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis.
Dev Dyn 2017;
246:1015-1026. [PMID:
28791750 DOI:
10.1002/dvdy.24563]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 08/02/2017] [Accepted: 08/07/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND
Craniofacial anomalies involve defective pharyngeal arch development and neural crest function. Copy number variation at 1p35, containing histone deacetylase 1 (Hdac1), or 6q21-22, containing Hdac2, are implicated in patients with craniofacial defects, suggesting an important role in guiding neural crest development. However, the roles of Hdac1 and Hdac2 within neural crest cells remain unknown.
RESULTS
The neural crest and its derivatives express both Hdac1 and Hdac2 during early murine development. Ablation of Hdac1 and Hdac2 within murine neural crest progenitor cells cause severe hemorrhage, atrophic pharyngeal arches, defective head morphogenesis, and complete embryonic lethality. Embryos lacking Hdac1 and Hdac2 in the neural crest exhibit decreased proliferation and increased apoptosis in both the neural tube and the first pharyngeal arch. Mechanistically, loss of Hdac1 and Hdac2 upregulates cyclin-dependent kinase inhibitors Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, Cdkn2c, and Tp53 within the first pharyngeal arch.
CONCLUSIONS
Our results show that Hdac1 and Hdac2 function redundantly within the neural crest to regulate proliferation and the development of the pharyngeal arches by means of repression of cyclin-dependent kinase inhibitors. Developmental Dynamics 246:1015-1026, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Zachary J Milstone
- Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.,Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
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- Grace Lawson
- Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
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- Chinmay M Trivedi
- Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.,Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.,Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts
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29
Han SH, Shim S, Kim MJ, Shin HY, Jang WS, Lee SJ, Jin YW, Lee SS, Lee SB, Park S. Long-term culture-induced phenotypic difference and efficient cryopreservation of small intestinal organoids by treatment timing of Rho kinase inhibitor.
World J Gastroenterol 2017;
23:964-975. [PMID:
28246470 PMCID:
PMC5311106 DOI:
10.3748/wjg.v23.i6.964]
[Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/03/2016] [Accepted: 11/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM
To investigate a suitable long-term culture system and optimal cryopreservation of intestinal organoid to improve organoid-based therapy by acquiring large numbers of cells.
METHODS
Crypts were isolated from jejunum of C57BL/6 mouse. Two hundred crypts were cultured in organoid medium with either epidermal growth factor/Noggin/R-spondin1 (ENR) or ENR/CHIR99021/VPA (ENR-CV). For subculture, organoids cultured on day 7 were passaged using enzyme-free cell dissociation buffer (STEMCELL Technologies). The passage was performed once per week until indicated passage. For cryopreservation, undissociated and dissociated organoids were resuspended in freezing medium with or without Rho kinase inhibitor subjected to different treatment times. The characteristics of intestinal organoids upon extended passage and freeze-thaw were analyzed using EdU staining, methyl thiazolyl tetrazolium assay, qPCR and time-lapse live cell imaging.
RESULTS
We established a three-dimensional culture system for murine small intestinal organoids using ENR and ENR-CV media. Both conditions yielded organoids with a crypt-villus architecture exhibiting Lgr5+ cells and differentiated intestinal epithelial cells as shown by morphological and biochemical analysis. However, during extended passage (more than 3 mo), a comparative analysis revealed that continuous passaging under ENR-CV conditions, but not ENR conditions induced phenotypic changes as observed by morphological transition, reduced numbers of Lgr5+ cells and inconsistent expression of markers for differentiated intestinal epithelial cell types. We also found that recovery of long-term cryopreserved organoids was significantly affected by the organoid state, i.e., whether dissociation was applied, and the timing of treatment with the Rho-kinase inhibitor Y-27632. Furthermore, the retention of typical morphological characteristics of intestinal organoids such as the crypt-villus structure from freeze-thawed cells was observed by live cell imaging.
CONCLUSION
The maintenance of the characteristics of intestinal organoids upon extended passage is mediated by ENR condition, but not ENR-CV condition. Identified long-term cryopreservation may contribute to the establishment of standardized cryopreservation protocols for intestinal organoids for use in clinical applications.
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30
Woo V, Alenghat T. Host-microbiota interactions: epigenomic regulation.
Curr Opin Immunol 2017;
44:52-60. [PMID:
28103497 DOI:
10.1016/j.coi.2016.12.001]
[Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 12/02/2016] [Accepted: 12/08/2016] [Indexed: 12/14/2022]
Abstract
The coevolution of mammalian hosts and their commensal microbiota has led to the development of complex symbiotic relationships between resident microbes and mammalian cells. Epigenomic modifications enable host cells to alter gene expression without modifying the genetic code, and therefore represent potent mechanisms by which mammalian cells can transcriptionally respond, transiently or stably, to environmental cues. Advances in genome-wide approaches are accelerating our appreciation of microbial influences on host physiology, and increasing evidence highlights that epigenomics represent a level of regulation by which the host integrates and responds to microbial signals. In particular, bacterial-derived short chain fatty acids have emerged as one clear link between how the microbiota intersects with host epigenomic pathways. Here we review recent findings describing crosstalk between the microbiota and epigenomic pathways in multiple mammalian cell populations. Further, we discuss interesting links that suggest that the scope of our understanding of epigenomic regulation in the host-microbiota relationship is still in its infancy.
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Affiliation(s)
- Vivienne Woo
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
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- Theresa Alenghat
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
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31
Hollins AJ, Parry L. Long-Term Culture of Intestinal Cell Progenitors: An Overview of Their Development, Application, and Associated Technologies.
CURRENT PATHOBIOLOGY REPORTS 2016;
4:209-219. [PMID:
27882268 PMCID:
PMC5101250 DOI:
10.1007/s40139-016-0119-1]
[Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW
Long-term culture of adult progenitor cells in 3D is a recently emerging technology that inhabits the space between 2D cell lines and organ slice culture.
RECENT FINDINGS
Adaptations to defined media components in the wake of advances in ES and iPS cell culture has led to the identification of conditions that maintained intestinal cell progenitors in culture. These conditions retain cellular heterogeneity of the normal or tumour tissue, and the cultures have been shown to be genetically stable, such that substantial biobanks are being created from patient derived material. This coupled with advances in analytical tools has generated a field, characterized by the term "organoid culture", that has huge potential for advancing drug discovery, regenerative medicine, and furthering the understanding of fundamental intestinal biology.
SUMMARY
In this review, we describe the approaches available for the long-term culture of intestinal cells from normal and diseased tissue, the current challenges, and how the technology is likely to develop further.
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Affiliation(s)
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- Lee Parry
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, CF24 4HQ UK
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32
Schilderink R, Verseijden C, Seppen J, Muncan V, van den Brink GR, Lambers TT, van Tol EA, de Jonge WJ. The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC.
Am J Physiol Gastrointest Liver Physiol 2016;
310:G1138-46. [PMID:
27151945 DOI:
10.1152/ajpgi.00411.2015]
[Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 04/27/2016] [Indexed: 01/31/2023]
Abstract
In the intestinal mucosa, retinoic acid (RA) is a critical signaling molecule. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFAs) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFAs contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. With the use of human and mouse epithelial cell lines and primary enteroids, we studied the effect of SCFAs on the production of RA. Functional RA conversion was analyzed by Adlefluor activity assays. Butyrate (0-20 mM), in contrast to other SCFAs, dose dependently induced aldh1a1 or aldh1a3 transcript expression and increased RA conversion in human and mouse epithelial cells. Epithelial cell line data were replicated in intestinal organoids. In these organoids, butyrate (2-5 mM) upregulated aldh1a3 expression (36-fold over control), whereas aldh1a1 was not significantly affected. Butyrate enhanced maturation markers (Mucin-2 and villin) but did not consistently affect stemness markers or other Wnt target genes (lgr5, olfm4, ascl2, cdkn1). In enteroids, the stimulation of RA production by SCFA was mimicked by inhibitors of histone deacetylase 3 (HDAC3) but not by HDAC1/2 inhibitors nor by agonists of butyrate receptors G-protein-coupled receptor (GPR)43 or GPR109A, indicating that butyrate stimulates RA production via HDAC3 inhibition. We conclude that the SCFA butyrate inhibits HDAC3 and thereby supports epithelial RA production.
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Affiliation(s)
- Ronald Schilderink
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands
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- Caroline Verseijden
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands
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- Jurgen Seppen
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands
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- Vanesa Muncan
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands
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- Gijs R van den Brink
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; and
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- Tim T Lambers
- Mead Johnson Pediatric Nutrition Institute, Nijmegen, the Netherlands
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- Eric A van Tol
- Mead Johnson Pediatric Nutrition Institute, Nijmegen, the Netherlands
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- Wouter J de Jonge
- Tytgat Institute for Gastrointestinal and Liver Research, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands; and
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33
Roostaee A, Benoit YD, Boudjadi S, Beaulieu JF. Epigenetics in Intestinal Epithelial Cell Renewal.
J Cell Physiol 2016;
231:2361-7. [PMID:
27061836 PMCID:
PMC5074234 DOI:
10.1002/jcp.25401]
[Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/05/2016] [Indexed: 12/15/2022]
Abstract
A controlled balance between cell proliferation and differentiation is essential to maintain normal intestinal tissue renewal and physiology. Such regulation is powered by several intracellular pathways that are translated into the establishment of specific transcription programs, which influence intestinal cell fate along the crypt-villus axis. One important check-point in this process occurs in the transit amplifying zone of the intestinal crypts where different signaling pathways and transcription factors cooperate to manage cellular proliferation and differentiation, before secretory or absorptive cell lineage terminal differentiation. However, the importance of epigenetic modifications such as histone methylation and acetylation in the regulation of these processes is still incompletely understood. There have been recent advances in identifying the impact of histone modifications and chromatin remodelers on the proliferation and differentiation of normal intestinal crypt cells. In this review we discuss recent discoveries on the role of the cellular epigenome in intestinal cell fate, development, and tissue renewal. J. Cell. Physiol. 231: 2361-2367, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
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Affiliation(s)
- Alireza Roostaee
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Yannick D Benoit
- Faculty of Health Sciences, McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
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- Salah Boudjadi
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Jean-François Beaulieu
- Faculty of Medicine and Health Sciences, Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology, Université de Sherbrooke, Sherbrooke, Québec, Canada
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34
Gonneaud A, Turgeon N, Boudreau F, Perreault N, Rivard N, Asselin C. Distinct Roles for Intestinal Epithelial Cell-Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis.
J Cell Physiol 2016;
231:436-48. [PMID:
26174178 DOI:
10.1002/jcp.25090]
[Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 07/07/2015] [Indexed: 02/06/2023]
Abstract
The intestinal epithelium responds to and transmits signals from the microbiota and the mucosal immune system to insure intestinal homeostasis. These interactions are in part conveyed by epigenetic modifications, which respond to environmental changes. Protein acetylation is an epigenetic signal regulated by histone deacetylases, including Hdac1 and Hdac2. We have previously shown that villin-Cre-inducible intestinal epithelial cell (IEC)-specific Hdac1 and Hdac2 deletions disturb intestinal homeostasis. To determine the role of Hdac1 and Hdac2 in the regulation of IEC function and the establishment of the dual knockout phenotype, we have generated villin-Cre murine models expressing one Hdac1 allele without Hdac2, or one Hdac2 allele without Hdac1. We have also investigated the effect of short-term deletion of both genes in naphtoflavone-inducible Ah-Cre and tamoxifen-inducible villin-Cre(ER) mice. Mice with one Hdac1 allele displayed normal tissue architecture, but increased sensitivity to DSS-induced colitis. In contrast, mice with one Hdac2 allele displayed intestinal architecture defects, increased proliferation, decreased goblet cell numbers as opposed to Paneth cells, increased immune cell infiltration associated with fibrosis, and increased sensitivity to DSS-induced colitis. In comparison to dual knockout mice, intermediary activation of Notch, mTOR, and Stat3 signaling pathways was observed. While villin-Cre(ER) Hdac1 and Hdac2 deletions led to an impaired epithelium and differentiation defects, Ah-Cre-mediated deletion resulted in blunted proliferation associated with the induction of a DNA damage response. Our results suggest that IEC determination and intestinal homeostasis are highly dependent on Hdac1 and Hdac2 activity levels, and that changes in the IEC acetylome may alter the mucosal environment.
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Affiliation(s)
- Alexis Gonneaud
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Naomie Turgeon
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- François Boudreau
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Nathalie Perreault
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Nathalie Rivard
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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- Claude Asselin
- Département d'anatomie et biologie cellulaire, Pavillon de recherche appliquée sur le cancer, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
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35
Abstract
Colorectal cancer stem cells (CSCs) were initially considered to be a subset of undifferentiated tumor cells with well-defined phenotypic and molecular markers. However, emerging evidence indicates instead that colorectal CSCs are heterogeneous subsets of tumor cells that are continuously reshaped by the dynamic interactions between genetic, epigenetic, and immune factors in the tumor microenvironment. Thus, the colorectal CSC phenotypes and responsiveness to therapy may not only be a tumor cell-intrinsic feature, but also depend on tumor-extrinsic microenvironmental factors. Furthermore, emerging evidence also implicates colorectal CSCs in potential immune evasion. Therefore, understanding how colorectal CSC-intrinsic mechanisms cooperate with the extrinsic microenvironmental factors to dynamically shape colorectal CSC resistance to chemotherapy and immunotherapy holds great promise for development of targeted CSC therapies of advanced human CRC.
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36
Abstract
Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This Review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease.
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Affiliation(s)
- Isabel Beerman
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02116, USA
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- Derrick J Rossi
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02116, USA.
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