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Babu MA, Jyothi S R, Kaur I, Kumar S, Sharma N, Kumar MR, Rajput P, Ali H, Gupta G, Subramaniyan V, Wong LS, Kumarasamy V. The role of GATA4 in mesenchymal stem cell senescence: A new frontier in regenerative medicine. Regen Ther 2025; 28:214-226. [PMID: 39811069 PMCID: PMC11731776 DOI: 10.1016/j.reth.2024.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025] Open
Abstract
The Mesenchymal Stem Cell (MSC) is a multipotent progenitor cell with known differentiation potential towards various cell lineage, making it an appealing candidate for regenerative medicine. One major contributing factor to age-related MSC dysfunction is cellular senescence, which is the hallmark of relatively irreversible growth arrest and changes in functional properties. GATA4, a zinc-finger transcription factor, emerges as a critical regulator in MSC biology. Originally identified as a key regulator of heart development and specification, GATA4 has since been connected to several aspects of cellular processes, including stem cell proliferation and differentiation. Accumulating evidence suggests that the involvement of GATA4-nuclear signalizing in the process of MSC senescence-related traits may contribute to age-induced alterations in MSC behavior. GATA4 emerged as the central player in MSC senescence, interacting with several signaling pathways. Studies have shown that GATA4 expression is reduced with age in MSCs, which is associated with increased expression levels of senescence markers and impaired regenerative potential. At the mechanistic level, GATA4 regulates the expression of genes involved in cell cycle regulation, DNA repair, and oxidative stress response, thereby influencing the senescence phenotype in MSCs. The findings underscore the critical function of GATA4 in MSC homeostasis and suggest a promising new target to restore stem cell function during aging and disease. A better understanding of the molecular mechanisms that underlie GATA4 mediated modulation of MSC senescence would provide an opportunity to develop new therapies to revitalize old MSCs to increase their regenerative function for therapeutic purposes in regenerative medicine.
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Affiliation(s)
- M. Arockia Babu
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Renuka Jyothi S
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
| | - Irwanjot Kaur
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Sachin Kumar
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Naveen Sharma
- Chandigarh Pharmacy College, Chandigarh Group of College, Jhanjeri, Mohali, 140307, Punjab, India
| | - M. Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Pranchal Rajput
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Malaysia
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Cheras, Kuala Lumpur, Malaysia
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Burgon PG, Weldrick JJ, Talab OMSA, Nadeer M, Nomikos M, Megeney LA. Regulatory Mechanisms That Guide the Fetal to Postnatal Transition of Cardiomyocytes. Cells 2023; 12:2324. [PMID: 37759546 PMCID: PMC10528641 DOI: 10.3390/cells12182324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Heart disease remains a global leading cause of death and disability, necessitating a comprehensive understanding of the heart's development, repair, and dysfunction. This review surveys recent discoveries that explore the developmental transition of proliferative fetal cardiomyocytes into hypertrophic postnatal cardiomyocytes, a process yet to be well-defined. This transition is key to the heart's growth and has promising therapeutic potential, particularly for congenital or acquired heart damage, such as myocardial infarctions. Although significant progress has been made, much work is needed to unravel the complex interplay of signaling pathways that regulate cardiomyocyte proliferation and hypertrophy. This review provides a detailed perspective for future research directions aimed at the potential therapeutic harnessing of the perinatal heart transitions.
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Affiliation(s)
- Patrick G. Burgon
- Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar
| | - Jonathan J. Weldrick
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
| | | | - Muhammad Nadeer
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Michail Nomikos
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Lynn A. Megeney
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
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Cruciani S, Delitala AP, Cossu ML, Ventura C, Maioli M. Management of Obesity and Obesity-Related Disorders: From Stem Cells and Epigenetics to Its Treatment. Int J Mol Sci 2023; 24:2310. [PMID: 36768633 PMCID: PMC9916844 DOI: 10.3390/ijms24032310] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/26/2023] Open
Abstract
Obesity is a complex worldwide disease, characterized by an abnormal or excessive fat accumulation. The onset of this pathology is generally linked to a complex network of interactions among genetic and environmental factors, aging, lifestyle, and diets. During adipogenesis, several regulatory mechanisms and transcription factors are involved. As fat cells grow, adipose tissue becomes increasingly large and dysfunctional, losing its endocrine function, secreting pro-inflammatory cytokines, and recruiting infiltrating macrophages. This long-term low-grade systemic inflammation results in insulin resistance in peripheral tissues. In this review we describe the main mechanisms involved in adipogenesis, from a physiological condition to obesity. Current therapeutic strategies for the management of obesity and the related metabolic syndrome are also reported.
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Affiliation(s)
- Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
- Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Viale delle Medaglie d’Oro 305, 00136 Roma, Italy
| | | | - Maria Laura Cossu
- General Surgery Unit 2 “Clinica Chirurgica” Medical, Surgical and Experimental Sciences Department, University of Sassari, 07100 Sassari, Italy
| | - Carlo Ventura
- National Laboratory of Molecular Biology and Stem Cell Engineering, Eldor Lab, Istituto Nazionale di Biostrutture e Biosistemi (INBB), Via di Corticella 183, 40128 Bologna, Italy
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
- Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Viale delle Medaglie d’Oro 305, 00136 Roma, Italy
- Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
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Tcf12 is required to sustain myogenic genes synergism with MyoD by remodelling the chromatin landscape. Commun Biol 2022; 5:1201. [DOI: 10.1038/s42003-022-04176-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 10/26/2022] [Indexed: 11/11/2022] Open
Abstract
AbstractMuscle stem cells (MuSCs) are essential for skeletal muscle development and regeneration, ensuring muscle integrity and normal function. The myogenic proliferation and differentiation of MuSCs are orchestrated by a cascade of transcription factors. In this study, we elucidate the specific role of transcription factor 12 (Tcf12) in muscle development and regeneration based on loss-of-function studies. Muscle-specific deletion of Tcf12 cause muscle weight loss owing to the reduction of myofiber size during development. Inducible deletion of Tcf12 specifically in adult MuSCs delayed muscle regeneration. The examination of MuSCs reveal that Tcf12 deletion resulted in cell-autonomous defects during myogenesis and Tcf12 is necessary for proper myogenic gene expression. Mechanistically, TCF12 and MYOD work together to stabilise chromatin conformation and sustain muscle cell fate commitment-related gene and chromatin architectural factor expressions. Altogether, our findings identify Tcf12 as a crucial regulator of MuSCs chromatin remodelling that regulates muscle cell determination and participates in skeletal muscle development and regeneration.
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Jiang L, Liang J, Huang W, Ma J, Park KH, Wu Z, Chen P, Zhu H, Ma JJ, Cai W, Paul C, Niu L, Fan GC, Wang HS, Kanisicak O, Xu M, Wang Y. CRISPR activation of endogenous genes reprograms fibroblasts into cardiovascular progenitor cells for myocardial infarction therapy. Mol Ther 2022; 30:54-74. [PMID: 34678511 PMCID: PMC8753567 DOI: 10.1016/j.ymthe.2021.10.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/27/2021] [Accepted: 10/18/2021] [Indexed: 01/07/2023] Open
Abstract
Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic analysis showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a positive feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.
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Affiliation(s)
- Lin Jiang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jialiang Liang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jianyong Ma
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Ki Ho Park
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Zhichao Wu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Peng Chen
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Hua Zhu
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jian-Jie Ma
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Wenfeng Cai
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Christian Paul
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Liang Niu
- Division of Biostatistics and Bioinformatics, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Guo-Chang Fan
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Hong-Sheng Wang
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Onur Kanisicak
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Meifeng Xu
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Yigang Wang
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
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Garroni G, Balzano F, Cruciani S, Pala R, Coradduzza D, Azara E, Bellu E, Cossu ML, Ginesu GC, Carru C, Ventura C, Maioli M. Adipose-Derived Stem Cell Features and MCF-7. Cells 2021; 10:1754. [PMID: 34359925 PMCID: PMC8307920 DOI: 10.3390/cells10071754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/09/2021] [Accepted: 07/09/2021] [Indexed: 01/04/2023] Open
Abstract
Human adipose tissue-derived stem cells (hADSCs) are highly suitable for regeneration therapies being easily collected and propagated in vitro. The effects of different external factors and culturing conditions are able to affect hADSC proliferation, senescence, differentiation, and migration, even at the molecular level. In the present paper, we exposed hADSCs to an exhausted medium from the breast cancer cell line (MCF-7) to evaluate whether the soluble factors released by these cells may be able to induce changes in stem cell behavior. In particular, we investigated the expression of stemness-related genes (OCT4; Sox 2; Nanog), the cell-cycle regulators p21 (WAF1/CIP1) p53, epigenetic markers (DNMT1 and Sirt1), and autophagy-related proteins. From our results, we can infer that the exhausted medium from MCF-7 is able to influence the hADSCs behavior increasing the expression of stemness-related genes, cell proliferation, and autophagy. Polyamines detectable in MCF-7 exhausted medium could be related to the higher proliferation capability observed in hADSCs, suggesting direct crosstalk between these molecules and the observed changes in stem cell potency.
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Affiliation(s)
- Giuseppe Garroni
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Francesca Balzano
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Renzo Pala
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Donatella Coradduzza
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Emanuela Azara
- Institute of Biomolecular Chemistry, National Research Council, 07100 Sassari, Italy;
| | - Emanuela Bellu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Maria Laura Cossu
- Department of Medical, Surgical and Experimental Sciences, General Surgery Unit 2 “Clinica Chirurgica”, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy; (M.L.C.); (G.C.G.)
| | - Giorgio C. Ginesu
- Department of Medical, Surgical and Experimental Sciences, General Surgery Unit 2 “Clinica Chirurgica”, University of Sassari, Viale San Pietro 8, 07100 Sassari, Italy; (M.L.C.); (G.C.G.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
| | - Carlo Ventura
- Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems-Eldor Lab, Innovation Accelerator, Consiglio Nazionale Delle Ricerche, 40129 Bologna, Italy;
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; (G.G.); (F.B.); (S.C.); (R.P.); (D.C.); (E.B.); (C.C.)
- Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy
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Ballarin L, Karahan A, Salvetti A, Rossi L, Manni L, Rinkevich B, Rosner A, Voskoboynik A, Rosental B, Canesi L, Anselmi C, Pinsino A, Tohumcu BE, Jemec Kokalj A, Dolar A, Novak S, Sugni M, Corsi I, Drobne D. Stem Cells and Innate Immunity in Aquatic Invertebrates: Bridging Two Seemingly Disparate Disciplines for New Discoveries in Biology. Front Immunol 2021; 12:688106. [PMID: 34276677 PMCID: PMC8278520 DOI: 10.3389/fimmu.2021.688106] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022] Open
Abstract
The scopes related to the interplay between stem cells and the immune system are broad and range from the basic understanding of organism's physiology and ecology to translational studies, further contributing to (eco)toxicology, biotechnology, and medicine as well as regulatory and ethical aspects. Stem cells originate immune cells through hematopoiesis, and the interplay between the two cell types is required in processes like regeneration. In addition, stem and immune cell anomalies directly affect the organism's functions, its ability to cope with environmental changes and, indirectly, its role in ecosystem services. However, stem cells and immune cells continue to be considered parts of two branches of biological research with few interconnections between them. This review aims to bridge these two seemingly disparate disciplines towards much more integrative and transformative approaches with examples deriving mainly from aquatic invertebrates. We discuss the current understanding of cross-disciplinary collaborative and emerging issues, raising novel hypotheses and comments. We also discuss the problems and perspectives of the two disciplines and how to integrate their conceptual frameworks to address basic equations in biology in a new, innovative way.
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Affiliation(s)
| | - Arzu Karahan
- Middle East Technical University, Institute of Marine Sciences, Erdemli, Mersin, Turkey
| | - Alessandra Salvetti
- Department of Clinical and Experimental Medicine, Unit of Experimental Biology and Genetics, University of Pisa, Pisa, Italy
| | - Leonardo Rossi
- Department of Clinical and Experimental Medicine, Unit of Experimental Biology and Genetics, University of Pisa, Pisa, Italy
| | - Lucia Manni
- Department of Biology, University of Padua, Padua, Italy
| | - Baruch Rinkevich
- Department of Biology, Israel Oceanographic and Limnological Research, National Institute of Oceanography, Haifa, Israel
| | - Amalia Rosner
- Department of Biology, Israel Oceanographic and Limnological Research, National Institute of Oceanography, Haifa, Israel
| | - Ayelet Voskoboynik
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
- Department of Biology, Stanford University, Hopkins Marine Station, Pacific Grove, CA, United States
- Department of Biology, Chan Zuckerberg Biohub, San Francisco, CA, United States
| | - Benyamin Rosental
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Center for Regenerative Medicine and Stem Cells, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Laura Canesi
- Department of Earth Environment and Life Sciences (DISTAV), University of Genoa, Genoa, Italy
| | - Chiara Anselmi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
- Department of Biology, Stanford University, Hopkins Marine Station, Pacific Grove, CA, United States
| | - Annalisa Pinsino
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy
| | - Begüm Ece Tohumcu
- Middle East Technical University, Institute of Marine Sciences, Erdemli, Mersin, Turkey
| | - Anita Jemec Kokalj
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Andraž Dolar
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Sara Novak
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Michela Sugni
- Department of Environmental Science and Policy, University of Milan, Milan, Italy
| | - Ilaria Corsi
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, Italy
| | - Damjana Drobne
- Department of Biology, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
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Shafi O. Switching of vascular cells towards atherogenesis, and other factors contributing to atherosclerosis: a systematic review. Thromb J 2020; 18:28. [PMID: 33132762 PMCID: PMC7592591 DOI: 10.1186/s12959-020-00240-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 09/23/2020] [Indexed: 12/17/2022] Open
Abstract
Background Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing. Methods Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells. Results Atherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET - 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl - 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others.This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis. Conclusion The development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity.The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in 'switching' of vascular cells towards atherosclerosis.
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Affiliation(s)
- Ovais Shafi
- Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan
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9
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Duddu S, Chakrabarti R, Ghosh A, Shukla PC. Hematopoietic Stem Cell Transcription Factors in Cardiovascular Pathology. Front Genet 2020; 11:588602. [PMID: 33193725 PMCID: PMC7596349 DOI: 10.3389/fgene.2020.588602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Transcription factors as multifaceted modulators of gene expression that play a central role in cell proliferation, differentiation, lineage commitment, and disease progression. They interact among themselves and create complex spatiotemporal gene regulatory networks that modulate hematopoiesis, cardiogenesis, and conditional differentiation of hematopoietic stem cells into cells of cardiovascular lineage. Additionally, bone marrow-derived stem cells potentially contribute to the cardiovascular cell population and have shown potential as a therapeutic approach to treat cardiovascular diseases. However, the underlying regulatory mechanisms are currently debatable. This review focuses on some key transcription factors and associated epigenetic modifications that modulate the maintenance and differentiation of hematopoietic stem cells and cardiac progenitor cells. In addition to this, we aim to summarize different potential clinical therapeutic approaches in cardiac regeneration therapy and recent discoveries in stem cell-based transplantation.
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Affiliation(s)
| | | | | | - Praphulla Chandra Shukla
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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10
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De N, Nandi M, Banik S, Roy S. Bi-stability of the master gene regulatory network of the common dendritic precursor cell: Implications for cell differentiation. IUBMB Life 2020; 72:2225-2232. [PMID: 32790022 DOI: 10.1002/iub.2355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 07/10/2020] [Indexed: 11/08/2022]
Abstract
In cell lineage commitment decisions, a gene regulatory network (GRN) consisting of a limited number of transcription factors forms the regulatory pivot. Myeloid lineage dendritic cells or DCs are specialized cells having the antigen-presenting ability and are of immense importance in immune surveillance. In this report, we analyze the GRN that governs the lineage commitment of Common DC Progenitor (CDP) cells to conventional dendritic cells (cDC) and plasmacytoid dendritic cells (pDC). We have analyzed the quantitative behavior of the master regulatory circuit of CDP that governs the lineage commitment. Simulations showed that the GRN displays a bi-stable behavior within a range of parameter values. Several transcription factors, PU.1, IRF8, Flt3, and Stat3, whose concentrations vary significantly in the two steady states, appear to be the key players. We hypothesize that the two stable steady states are precursors of cDC and pDC, and the variation of concentration of these key transcription factors in the two states may be responsible for early events in lineage commitment.
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Affiliation(s)
- Nayan De
- Department of Biophysics, Bose Institute, Kolkata, India
| | - Mintu Nandi
- Department of Chemistry, University of Calcutta, Kolkata, India
| | - Suman Banik
- Department of Chemistry, Bose Institute, Kolkata, India
| | - Siddhartha Roy
- Department of Biophysics, Bose Institute, Kolkata, India
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11
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Zamani ARN, Saberianpour S, Geranmayeh MH, Bani F, Haghighi L, Rahbarghazi R. Modulatory effect of photobiomodulation on stem cell epigenetic memory: a highlight on differentiation capacity. Lasers Med Sci 2019; 35:299-306. [PMID: 31494789 DOI: 10.1007/s10103-019-02873-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023]
Abstract
Differentiation potential of stem cells into various lineages makes these cells as promising sources to treat multiple diseases. In this regard, the use of different strategies and protocols to increase differentiation capacity is highly demanded. Low-level laser therapy, a relatively noninvasive technique, has the capacity to accelerate the healing of numerous injuries and a portion of restorative capacity could be correlated with the stem cell activation and differentiation. Several mechanisms have been diagnosed to participate in orientation of stem cells to functional mature cells. Among them, the status of DNA methylation orchestrates the maintenance of tissue-specific gene expression during the differentiation procedure. DNA methylation is a momentous event in embryogenesis and functional maturation. This review article highlighted the potency of laser irradiation (low-level intensities) in the differentiation of stem cells by modulation of methylation. The analysis of these modalities could help us to understand the underlying mechanisms participating in the therapeutic effects of photobiomodulation.
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Affiliation(s)
| | - Shirin Saberianpour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Farhad Bani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Haghighi
- Department of Parasitology and Mycology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Human osteogenic differentiation in Space: proteomic and epigenetic clues to better understand osteoporosis. Sci Rep 2019; 9:8343. [PMID: 31171801 PMCID: PMC6554341 DOI: 10.1038/s41598-019-44593-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/15/2019] [Indexed: 12/12/2022] Open
Abstract
In the frame of the VITA mission of the Italian Space Agency (ASI), we addressed the problem of Space osteoporosis by using human blood-derived stem cells (BDSCs) as a suitable osteogenic differentiation model. In particular, we investigated proteomic and epigenetic changes in BDSCs during osteoblastic differentiation induced by rapamycin under microgravity conditions. A decrease in the expression of 4 embryonic markers (Sox2, Oct3/4, Nanog and E-cadherin) was found to occur to a larger extent on board the ISS than on Earth, along with an earlier activation of the differentiation process towards the osteogenic lineage. The changes in the expression of 4 transcription factors (Otx2, Snail, GATA4 and Sox17) engaged in osteogenesis supported these findings. We then ascertained whether osteogenic differentiation of BDSCs could depend on epigenetic regulation, and interrogated changes of histone H3 that is crucial in this type of gene control. Indeed, we found that H3K4me3, H3K27me2/3, H3K79me2/3 and H3K9me2/3 residues are engaged in cellular reprogramming that drives gene expression. Overall, we suggest that rapamycin induces transcriptional activation of BDSCs towards osteogenic differentiation, through increased GATA4 and Sox17 that modulate downstream transcription factors (like Runx2), critical for bone formation. Additional studies are warranted to ascertain the possible exploitation of these data to identify new biomarkers and therapeutic targets to treat osteoporosis, not only in Space but also on Earth.
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13
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Chahal G, Tyagi S, Ramialison M. Navigating the non-coding genome in heart development and Congenital Heart Disease. Differentiation 2019; 107:11-23. [PMID: 31102825 DOI: 10.1016/j.diff.2019.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 01/14/2019] [Accepted: 05/06/2019] [Indexed: 12/12/2022]
Abstract
Congenital Heart Disease (CHD) is characterised by a wide range of cardiac defects, from mild to life-threatening, which occur in babies worldwide. To date, there is no cure to CHD, however, progress in surgery has reduced its mortality allowing children affected by CHD to reach adulthood. In an effort to understand its genetic basis, several studies involving whole-genome sequencing (WGS) of patients with CHD have been undertaken and generated a great wealth of information. The majority of putative causative mutations identified in WGS studies fall into the non-coding part of the genome. Unfortunately, due to the lack of understanding of the function of these non-coding mutations, it is challenging to establish a causal link between the non-coding mutation and the disease. Thus, here we review the state-of-the-art approaches to interpret non-coding mutations in the context of CHD and address the following questions: What are the non-coding sequences important for cardiac function? Which technologies are used to identify them? Which resources are available to analyse them? What mutations are expected in these non-coding sequences? Learning from developmental process, what is their expected role in CHD?
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Affiliation(s)
- Gulrez Chahal
- Australian Regenerative Medicine Institute (ARMI), 15 Innovation Walk, Monash University, Wellington Road, Clayton, 3800, VIC, Australia; Systems Biology Institute (SBI), Wellington Road, Clayton, 3800, VIC, Australia
| | - Sonika Tyagi
- School of Biological Sciences, Monash University, Wellington Road, Clayton, 3800, VIC, Australia; Australian Genome Research Facility, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
| | - Mirana Ramialison
- Australian Regenerative Medicine Institute (ARMI), 15 Innovation Walk, Monash University, Wellington Road, Clayton, 3800, VIC, Australia; Systems Biology Institute (SBI), Wellington Road, Clayton, 3800, VIC, Australia.
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14
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Daum R, Brauchle EM, Berrio DAC, Jurkowski TP, Schenke-Layland K. Non-invasive detection of DNA methylation states in carcinoma and pluripotent stem cells using Raman microspectroscopy and imaging. Sci Rep 2019; 9:7014. [PMID: 31065074 PMCID: PMC6504883 DOI: 10.1038/s41598-019-43520-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 04/26/2019] [Indexed: 11/09/2022] Open
Abstract
DNA methylation plays a critical role in the regulation of gene expression. Global DNA methylation changes occur in carcinogenesis as well as early embryonic development. However, the current methods for studying global DNA methylation levels are invasive and require sample preparation. The present study was designed to investigate the potential of Raman microspectroscopy and Raman imaging as non-invasive, marker-independent and non-destructive tools for the detection of DNA methylation in living cells. To investigate global DNA methylation changes, human colon carcinoma HCT116 cells, which were hypomorphic for DNA methyltransferase 1, therefore showing a lower global DNA methylation (DNMT1−/− cells), were compared to HCT116 wildtype cells. As a model system for early embryogenesis, murine embryonic stem cells were adapted to serum-free 2i medium, leading to a significant decrease in DNA methylation. Subsequently, 2i medium -adapted cells were compared to cells cultured in serum-containing medium. Raman microspectroscopy and imaging revealed significant differences between high- and low-methylated cell types. Higher methylated cells demonstrated higher relative intensities of Raman peaks, which can be assigned to the nucleobases and 5-methylcytosine. Principal component analysis detected distinguishable populations of high- and low-methylated samples. Based on the provided data we conclude that Raman microspectroscopy and imaging are suitable tools for the real-time, marker-independent and artefact-free investigation of the DNA methylation states in living cells.
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Affiliation(s)
- Ruben Daum
- Department of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, Silcherstr. 7/1, 72076, Tübingen, Germany.,The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany
| | - Eva M Brauchle
- Department of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, Silcherstr. 7/1, 72076, Tübingen, Germany.,The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany
| | - Daniel Alejandro Carvajal Berrio
- Department of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, Silcherstr. 7/1, 72076, Tübingen, Germany
| | - Tomasz P Jurkowski
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Katja Schenke-Layland
- Department of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University Tübingen, Silcherstr. 7/1, 72076, Tübingen, Germany. .,The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany. .,Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, 675 Charles E. Young Drive South, MRL 3645, Los Angeles, CA, USA.
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15
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H3K27me3 Depletion during Differentiation Promotes Myogenic Transcription in Porcine Satellite Cells. Genes (Basel) 2019; 10:genes10030231. [PMID: 30893875 PMCID: PMC6471710 DOI: 10.3390/genes10030231] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 02/23/2019] [Accepted: 03/11/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Porcine skeletal muscle satellite cells play important roles in myogenesis and muscle regeneration. Integrated analysis of transcriptome and histone modifications would reveal epigenomic roles in promoting myogenic differentiation in swine. METHODS Porcine satellite cells (PSCs) were isolated and in-vitro cultured from newborn piglets. RNA Sequencing (RNA-Seq) and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) experiments were performed using proliferating cells and terminal myotubes in order to interrogate the transcriptomic profiles, as well as the distribution of histone markers-H3K4me3, H3K27me3, and H3K27ac-and RNA polymerase II. RESULTS The study identified 917 differentially expressed genes during cell differentiation. The landscape of epigenetic marks was displayed on a genome-wide scale, which had globally shrunken. H3K27me3 reinforcement participated in obstructing the transcription of proliferation-related genes, while its depletion was closely related to the up-regulation of myogenic genes. Furthermore, the degree of H3K27me3 modification was dramatically reduced by 50%, and 139 myogenic genes were upregulated to promote cell differentiation. CONCLUSIONS The depletion of H3K27me3 was shown to promote porcine satellite cell differentiation through upregulating the transcription level of myogenic genes. Our findings in this study provide new insights of the epigenomic mechanisms occurring during myogenic differentiation, and shed light on chromatin states and the dynamics underlying myogenesis.
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16
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m 6A methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3/JAK2/STAT3 pathway in a YTHDF1/YTHDF2-orchestrated manner. Cell Death Dis 2019; 10:171. [PMID: 30787270 PMCID: PMC6382841 DOI: 10.1038/s41419-019-1417-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 12/18/2022]
Abstract
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, disease treatment, and organ transplantation. As the ethical issue of human ESCs and similarity of pig in human genome and physiological characteristics, the porcine iPSCs (piPSCs) have become an ideal alternative study model. N6-methyladenosine (m6A) methylation is the most prevalent modification in eukaryotic mRNAs, regulating the self-renewal and differentiation of pluripotency stem cells. However, the explicit m6A-regulating machinery remains controversial. Here, we demonstrate that m6A modification and its modulators play a crucial role in mediating piPSCs pluripotency. In brief, loss of METTL3 significantly impairs self-renewal and triggers differentiation of piPSCs by interfering JAK2 and SOCS3 expression, further inactivating JAK2-STAT3 pathway, which then blocks the transcription of KLF4 and SOX2. We identify that both of JAK2 and SOSC3 have m6A modification at 3'UTR by m6A-seq analysis. Dual-luciferase assay shows that METTL3 regulates JAK2 and SOCS3 expression in an m6A-dependent way. RIP-qPCR validates JAK2 and SOCS3 are the targets of YTHDF1 and YTHDF2, respectively. SiMETTL3 induced lower m6A levels of JAK2 and SOCS3 lead to the inhibition of YTHDF1-mediated JAK2 translation and the block of YTHDF2-dependent SOCS3 mRNA decay. Subsequently, the altered protein expressions of JAK2 and SOCS3 inhibit JAK2-STAT3 pathway and then the pluripotency of piPSCs. Collectively, our work uncovers the critical role of m6A modification and its modulators in regulating piPSCs pluripotency and provides insight into an orchestrated network linking the m6A methylation and SOCS3/JAK2/STAT3 pathway in pluripotency regulation.
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17
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5813147. [PMID: 30881594 PMCID: PMC6383393 DOI: 10.1155/2019/5813147] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/08/2018] [Indexed: 12/17/2022]
Abstract
Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.
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18
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Cheray M, Joseph B. Epigenetics Control Microglia Plasticity. Front Cell Neurosci 2018; 12:243. [PMID: 30123114 PMCID: PMC6085560 DOI: 10.3389/fncel.2018.00243] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 07/18/2018] [Indexed: 01/31/2023] Open
Abstract
Microglia, resident immune cells of the central nervous system, fulfill multiple functions in the brain throughout life. These microglial functions range from participation in innate and adaptive immune responses, involvement in the development of the brain and its homeostasis maintenance, to contribution to degenerative, traumatic, and proliferative diseases; and take place in the developing, the aging, the healthy, or the diseased brain. Thus, an impressive level of cellular plasticity, appears as a requirement for the pleiotropic biological functions of microglia. Epigenetic changes, including histone modifications or DNA methylation as well as microRNA expression, are important modifiers of gene expression, and have been involved in cell phenotype regulation and reprogramming and are therefore part of the mechanisms regulating cellular plasticity. Here, we review and discuss the epigenetic mechanisms, which are emerging as contributors to this microglial cellular plasticity and thereby can constitute interesting targets to modulate microglia associated brain diseases, including developmental diseases, neurodegenerative diseases as well as cancer.
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Affiliation(s)
- Mathilde Cheray
- Toxicology Unit, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden
| | - Bertrand Joseph
- Toxicology Unit, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden
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19
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Epigenetic modifications in the embryonic and induced pluripotent stem cells. Gene Expr Patterns 2018; 29:1-9. [PMID: 29625185 DOI: 10.1016/j.gep.2018.04.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 03/03/2018] [Accepted: 04/03/2018] [Indexed: 02/07/2023]
Abstract
Epigenetic modifications are involved in global reprogramming of the cell transcriptome. Therefore, synchronized major shifts in the expression of many genes could be achieved through epigenetic changes. The regulation of gene expression could be implemented by different epigenetic events including histone modifications, DNA methylation and chromatin remodelling. Interestingly, it has been documented that reprogramming of somatic cells to induced pluripotent stem (iPS) cells is also a typical example of epigenetic modifications. Additionally, epigenetic would determine the fates of almost all cells upon differentiation of stem cells into somatic cells. Currently, generation of iPS cells through epigenetic modifications is a routine laboratory practice. Despite all our knowledge, inconsistency in the results of reprogramming and differentiation of stem cells, highlight the need for more thorough investigation into the role of epigenetic modification in generation and maintenance of stem cells. Besides, subtle differences have been observed among different iPS cells and between iPS and ES cells. Although, a handful of detailed review regarding the status of epigenetics in stem cells has been published previously, in the current review, an abstracted and rather simplified view has been presented for those who want to gain a more general overview on this subject. However, almost all key references and ground breaking studies were included, which could be further explored to gain more in depth knowledge regarding this topic. The most dominant epigenetic changes have been presented followed by the impacts of such changes on the global gene expression. Epigenetic status in iPS and ES cells were compared. In addition to including the issues related to X-chromosome reactivation in the stem cells, we have also included loss of imprinting for some genes as a major drawback in generation of iPS cells. Finally, the overall impacts of epigenetic modifications on different aspects of stem cells has been discussed, including their use in cell therapy.
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20
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Lee S, Lee J, Chae S, Moon Y, Lee HY, Park B, Yang EG, Hwang D, Park H. Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia. Nucleic Acids Res 2017; 45:11643-11657. [PMID: 28977425 PMCID: PMC5714201 DOI: 10.1093/nar/gkx747] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 08/22/2017] [Indexed: 02/06/2023] Open
Abstract
Hypoxia increases both active and repressive histone methylation levels via decreased activity of histone demethylases. However, how such increases coordinately regulate induction or repression of hypoxia-responsive genes is largely unknown. Here, we profiled active and repressive histone tri-methylations (H3K4me3, H3K9me3, and H3K27me3) and analyzed gene expression profiles in human adipocyte-derived stem cells under hypoxia. We identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs) by hypoxia and clustered the DEGs and DMGs into four major groups. We found that each group of DEGs was predominantly associated with alterations in only one type among the three histone tri-methylations. Moreover, the four groups of DEGs were associated with different TFs and localization patterns of their predominant types of H3K4me3, H3K9me3 and H3K27me3. Our results suggest that the association of altered gene expression with prominent single-type histone tri-methylations characterized by different localization patterns and with different sets of TFs contributes to regulation of particular sets of genes, which can serve as a model for coordinated epigenetic regulation of gene expression under hypoxia.
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Affiliation(s)
- Seongyeol Lee
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Jieon Lee
- Department of Chemical Engineering, POSTECH, Pohang 37673, Republic of Korea
| | - Sehyun Chae
- Department of New Biology and Center for Plant Aging Research, Institute of Basic Science, DGIST, Daegu 42988, Republic of Korea
| | - Yunwon Moon
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Ho-Youl Lee
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Bongju Park
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Eun Gyeong Yang
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Daehee Hwang
- Department of Chemical Engineering, POSTECH, Pohang 37673, Republic of Korea.,Department of New Biology and Center for Plant Aging Research, Institute of Basic Science, DGIST, Daegu 42988, Republic of Korea
| | - Hyunsung Park
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
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21
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Tu HC, Lee GH, Hsiao TH, Kao TT, Wang TY, Tsai JN, Fu TF. One crisis, diverse impacts-Tissue-specificity of folate deficiency-induced circulation defects in zebrafish larvae. PLoS One 2017; 12:e0188585. [PMID: 29176804 PMCID: PMC5703520 DOI: 10.1371/journal.pone.0188585] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 11/09/2017] [Indexed: 12/17/2022] Open
Abstract
Folate (vitamin B9) is an essential nutrient required for cell survival, proliferation, differentiation and therefore embryogenesis. Folate deficiency has been associated with many diseases, including congenital heart diseases and megaloblastic anemia, yet the mechanisms underlying these remains elusive. Here, we examine the impact of folate deficiency on the development of the circulation system using a zebrafish transgenic line which displays inducible folate deficiency. Impaired hematopoiesis includes decreased hemoglobin levels, decreased erythrocyte number, increased erythrocyte size and aberrant c-myb expression pattern were observed in folate deficient embryos. Cardiac defects, including smaller chamber size, aberrant cardiac function and cmlc2 expression pattern, were also apparent in folate deficient embryos. Characterization of intracellular folate content in folate deficiency revealed a differential fluctuation among the different folate derivatives that carry a single carbon group at different oxidation levels. Rescue attempts by folic acid and nucleotides resulted in differential responses among affected tissues, suggesting that different pathomechanisms are involved in folate deficiency-induced anomalies in a tissue-specific manner. The results of the current study provide an explanation for the inconsistent outcome observed clinically in patients suffering from folate deficiency and/or receiving folate supplementation. This study also supports the use of this model for further research on the defective cardiogenesis and hematopoiesis caused by folate deficiency.
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Affiliation(s)
- Hung-Chi Tu
- The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Gang-Hui Lee
- The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Tsun-Hsien Hsiao
- The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Tseng-Ting Kao
- The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Tzu-Ya Wang
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Jen-Ning Tsai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Tzu-Fun Fu
- The Institute of Basic Medical Sciences, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, College of Medicine, Tainan, Taiwan
- * E-mail:
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22
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Abstract
Efficient cardiac regeneration is closely associated with the ability of cardiac myocytes to proliferate. Fetal or neonatal mouse hearts containing proliferating cardiac myocytes regenerate even extensive injuries, whereas adult hearts containing mostly post-mitotic cardiac myocytes have lost this ability. The same correlation is seen in some homoiotherm species such as teleost fish and urodelian amphibians leading to the hypothesis that cardiac myocyte proliferation is a major driver of heart regeneration. Although cardiomyocyte proliferation might not be the only prerequisite to restore full organ function after cardiac damage, induction of cardiac myocyte proliferation is an attractive therapeutic option to cure the injured heart and prevent heart failure. To (re)initiate cardiac myocyte proliferation in adult mammalian hearts, a thorough understanding of the molecular circuitry governing cardiac myocyte cell cycle regulation is required. Here, we review the current knowledge in the field focusing on the withdrawal of cardiac myocytes from the cell cycle during the transition from neonatal to adult stages.
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Affiliation(s)
- Xuejun Yuan
- From the Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (X.Y., T.B.); and Department of Internal Medicine II, Justus Liebig University Giessen, Member of the German Center for Cardiovascular Research (DZHK), Member of the German Center for Lung Research (DZL), Giessen, Germany (T.B.)
| | - Thomas Braun
- From the Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (X.Y., T.B.); and Department of Internal Medicine II, Justus Liebig University Giessen, Member of the German Center for Cardiovascular Research (DZHK), Member of the German Center for Lung Research (DZL), Giessen, Germany (T.B.).
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23
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Kar G, Kim JK, Kolodziejczyk AA, Natarajan KN, Torlai Triglia E, Mifsud B, Elderkin S, Marioni JC, Pombo A, Teichmann SA. Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression. Nat Commun 2017; 8:36. [PMID: 28652613 PMCID: PMC5484669 DOI: 10.1038/s41467-017-00052-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 04/28/2017] [Indexed: 11/09/2022] Open
Abstract
Polycomb repressive complexes (PRCs) are important histone modifiers, which silence gene expression; yet, there exists a subset of PRC-bound genes actively transcribed by RNA polymerase II (RNAPII). It is likely that the role of Polycomb repressive complex is to dampen expression of these PRC-active genes. However, it is unclear how this flipping between chromatin states alters the kinetics of transcription. Here, we integrate histone modifications and RNAPII states derived from bulk ChIP-seq data with single-cell RNA-sequencing data. We find that Polycomb repressive complex-active genes have greater cell-to-cell variation in expression than active genes, and these results are validated by knockout experiments. We also show that PRC-active genes are clustered on chromosomes in both two and three dimensions, and interactions with active enhancers promote a stabilization of gene expression noise. These findings provide new insights into how chromatin regulation modulates stochastic gene expression and transcriptional bursting, with implications for regulation of pluripotency and development.Polycomb repressive complexes modify histones but it is unclear how changes in chromatin states alter kinetics of transcription. Here, the authors use single-cell RNAseq and ChIPseq to find that actively transcribed genes with Polycomb marks have greater cell-to-cell variation in expression.
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Affiliation(s)
- Gozde Kar
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Jong Kyoung Kim
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
- Department of New Biology, DGIST, Daegu, 42988, Republic of Korea
| | - Aleksandra A Kolodziejczyk
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - Kedar Nath Natarajan
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
| | - Elena Torlai Triglia
- Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Robert Roessle Strasse, Berlin-Buch, 13125, Germany
| | - Borbala Mifsud
- Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK
- Department of Genetics, Evolution and Environment, University College London, Gower Street, London, WC1E 6BT, UK
- William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Sarah Elderkin
- Nuclear Dynamics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK
| | - John C Marioni
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | - Ana Pombo
- Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Robert Roessle Strasse, Berlin-Buch, 13125, Germany
| | - Sarah A Teichmann
- European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
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Yuan X, Qi H, Li X, Wu F, Fang J, Bober E, Dobreva G, Zhou Y, Braun T. Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice. J Clin Invest 2017; 127:2235-2248. [PMID: 28436940 DOI: 10.1172/jci88725] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 02/23/2017] [Indexed: 12/17/2022] Open
Abstract
Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases are attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. Here, we have demonstrated that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing islet 1 (ISL1) in the secondary heart field (SHF) are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating NK2 homeobox 5 (Nkx2.5), resulting in decreased cell proliferation and enhanced cardiomyocyte specification. We found that HIF1α formed a complex with the Notch effector hes family bHLH transcription factor 1 (HES1) and the protein deacetylase sirtuin 1 (SIRT1) at the Isl1 gene. This complex repressed Isl1 in the hypoxic heart tube or following induction of ectopic hypoxic responses. Subsequently, reduced Isl1 expression abrogated ISL1-dependent recruitment of histone deacetylases HDAC1/5, inhibiting Nkx2.5 expression. Inactivation of Sirt1 in ISL1+ CPCs blocked Isl1 suppression via the HIF1α/HES1/SIRT1 complex and prevented CHDs induced by pathological hypoxia. Our results indicate that spatial differences in oxygenation of the developing heart serve as signals to control CPC expansion and cardiac morphogenesis. We propose that physiological hypoxia coordinates homeostasis of CPCs, providing mechanistic explanations for some nongenetic causes of CHD.
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Ahmed ASI, Sheng MHC, Wasnik S, Baylink DJ, Lau KHW. Effect of aging on stem cells. World J Exp Med 2017; 7:1-10. [PMID: 28261550 PMCID: PMC5316899 DOI: 10.5493/wjem.v7.i1.1] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 11/19/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pluripotent stem cells have the remarkable self-renewal ability and are capable of differentiating into multiple diverse cells. There is increasing evidence that the aging process can have adverse effects on stem cells. As stem cells age, their renewal ability deteriorates and their ability to differentiate into the various cell types is altered. Accordingly, it is suggested aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various aging-associated disorders. Understanding the role of the aging process in deterioration of stem cell function is crucial, not only in understanding the pathophysiology of aging-associated disorders, but also in future development of novel effective stem cell-based therapies to treat aging-associated diseases. This review article first focuses on the basis of the various aging disease-related stem cell dysfunction. It then addresses the several concepts on the potential mechanism that causes aging-related stem cell dysfunction. It also briefly discusses the current potential therapies under development for aging-associated stem cell defects.
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27
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Garland T, Cadney MD, Waterland RA. Early-Life Effects on Adult Physical Activity: Concepts, Relevance, and Experimental Approaches. Physiol Biochem Zool 2016; 90:1-14. [PMID: 28051947 PMCID: PMC6397655 DOI: 10.1086/689775] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Locomotion is a defining characteristic of animal life and plays a crucial role in most behaviors. Locomotion involves physical activity, which can have far-reaching effects on physiology and neurobiology, both acutely and chronically. In human populations and in laboratory rodents, higher levels of physical activity are generally associated with positive health outcomes, although excessive exercise can have adverse consequences. Whether and how such relationships occur in wild animals is unknown. Behavioral variation among individuals arises from genetic and environmental factors and their interactions as well as from developmental programming (persistent effects of early-life environment). Although tremendous progress has been made in identifying genetic and environmental influences on individual differences in behavior, early-life effects are not well understood. Early-life effects can in some cases persist across multiple generations following a single exposure and, in principle, may constrain or facilitate the rate of evolution at multiple levels of biological organization. Understanding the mechanisms of such transgenerational effects (e.g., exposure to stress hormones in utero, inherited epigenetic alterations) may prove crucial to explaining unexpected and/or sex-specific responses to selection as well as limits to adaptation. One area receiving increased attention is early-life effects on adult physical activity. Correlational data from epidemiological studies suggest that early-life nutritional stress can (adversely) affect adult human activity levels and associated physiological traits (e.g., body composition, metabolic health). The few existing studies of laboratory rodents demonstrate that both maternal and early-life exercise can affect adult levels of physical activity and related phenotypes. Going forward, rodents offer many opportunities for experimental studies of (multigenerational) early-life effects, including studies that use maternal exposures and cross-fostering designs.
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Affiliation(s)
- Theodore Garland
- Department of Biology, University of California, Riverside, California 92521
| | - Marcell D. Cadney
- Department of Biology, University of California, Riverside, California 92521
| | - Robert A. Waterland
- Departments of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Houston, Texas 77030
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Abstract
Hematopoietic stem cells are endowed with a distinct potential to bolster self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. Both hematopoietic stem cells and mature cells have the same genome, but their gene expression is controlled by an additional layer of epigenetics such as DNA methylation and post-translational histone modifications, enabling each cell-type to acquire various forms and functions. Until recently, several studies have largely focussed on the transcription factors andniche factors for the understanding of the molecular mechanisms by which hematopoietic cells replicate and differentiate. Several lines of emerging evidence suggest that epigenetic modifications eventually result in a defined chromatin structure and an “individual” gene expression pattern, which play an essential role in the regulation of hematopoietic stem cell self-renewal and differentiation. Distinct epigenetic marks decide which sets of genes may be expressed and which genes are kept silent. Epigenetic mechanisms are interdependent and ensure lifelong production of blood and bone marrow, thereby contributing to stem cell homeostasis. The epigenetic analysis of hematopoiesis raises the exciting possibility that chromatin structure is dynamic enough for regulated expression of genes. Though controlled chromatin accessibility plays an essential role in maintaining blood homeostasis; mutations in chromatin impacts on the regulation of genes critical to the development of leukemia. In this review, we explored the contribution of epigenetic machinery which has implications for the ramification of molecular details of hematopoietic self-renewal for normal development and underlying events that potentially co-operate to induce leukemia.
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Affiliation(s)
- Shilpa Sharma
- Division of Stem Cell Gene Therapy Research, Institute of Nuclear Medicine & Allied Sciences (INMAS), Delhi, India
| | - Gangenahalli Gurudutta
- Division of Stem Cell Gene Therapy Research, Institute of Nuclear Medicine & Allied Sciences (INMAS), Delhi, India
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Wu Y, Zhang S, Yuan Q. N(6)-Methyladenosine Methyltransferases and Demethylases: New Regulators of Stem Cell Pluripotency and Differentiation. Stem Cells Dev 2016; 25:1050-9. [PMID: 27216987 DOI: 10.1089/scd.2016.0062] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The discovery of mammalian N(6)-methyladenosine (m(6)A) methyltransferases and demethylases has enriched our knowledge of the dynamic regulation of the most prevalent posttranscriptional RNA modification, m(6)A methylation. This reversible methylation process of adding and removing m(6)A marks on RNA has been shown to have broad biological functions in fine tuning cellular processes and gene expression. Recent studies have revealed a critical role for the currently known m(6)A methyltransferases and demethylases in regulating the pluripotency and differentiation of stem cells. These data establish a novel dimension in epigenetic regulation at the RNA level to affect mammalian cell fate.
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Affiliation(s)
- Yunshu Wu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China
| | - Shiwen Zhang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, China
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30
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The BRPF2/BRD1-MOZ complex is involved in retinoic acid-induced differentiation of embryonic stem cells. Exp Cell Res 2016; 346:30-9. [PMID: 27256846 DOI: 10.1016/j.yexcr.2016.05.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 05/24/2016] [Accepted: 05/27/2016] [Indexed: 12/13/2022]
Abstract
The scaffold protein BRPF2 (also called BRD1), a key component of histone acetyltransferase complexes, plays an important role in embryonic development, but its function in the differentiation of embryonic stem cells (ESCs) remains unknown. In the present study, we investigated whether BRPF2 is involved in mouse ESC differentiation. BRPF2 depletion resulted in abnormal formation of embryoid bodies, downregulation of differentiation-associated genes, and persistent maintenance of alkaline phosphatase activity even after retinoic acid-induced differentiation, indicating impaired differentiation of BRPF2-depleted ESCs. We also found reduced global acetylation of histone H3 lysine 14 (H3K14) in BRPF2-depleted ESCs, irrespective of differentiation status. Further, co-immunoprecipitation analysis revealed a physical association between BRPF2 and the histone acetyltransferase MOZ in differentiated ESCs, suggesting the role of BRPF2-MOZ complexes in ESC differentiation. Together, these results suggest that BRPF2-MOZ complexes play an important role in the differentiation of ESCs via H3K14 acetylation.
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31
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Retinoic acid receptor signaling preserves tendon stem cell characteristics and prevents spontaneous differentiation in vitrox. Stem Cell Res Ther 2016; 7:45. [PMID: 27001426 PMCID: PMC4802591 DOI: 10.1186/s13287-016-0306-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 01/12/2016] [Accepted: 03/04/2016] [Indexed: 02/07/2023] Open
Abstract
Background Previous studies have reported that adult mesenchymal stem cells (MSCs) tend to gradually lose their stem cell characteristics in vitro when placed outside their niche environment. They subsequently undergo spontaneous differentiation towards mesenchymal lineages after only a few passages. We observed a similar phenomenon with adult tendon stem cells (TSCs) where expression of key tendon genes such as Scleraxis (Scx), are being repressed with time in culture. We hypothesized that an environment able to restore or maintain Scleraxis expression could be of therapeutic interest for in vitro use and tendon cell-based therapies. Methods TSCs were isolated from human cadaveric Achilles tendon and expanded for 4 passages. A high content imaging assay that monitored the induction of Scx protein nuclear localization was used to screen ~1000 known drugs. Results We identified retinoic acid receptor (RAR) agonists as potent inducers of nuclear Scx in the small molecule screen. The upregulation correlated with improved maintenance of tendon stem cell properties through inhibition of spontaneous differentiation rather than the anticipated induction of tenogenic differentiation. Our results suggest that histone epigenetic modifications by RAR are driving this effect which is not likely only dependent on Scleraxis nuclear binding but also mediated through other key genes involved in stem cell self-renewal and differentiation. Furthermore, we demonstrate that the effect of RAR compounds on TSCs is reversible by revealing their multi-lineage differentiation ability upon withdrawal of the compound. Conclusion Based on these findings, RAR agonists could provide a valid approach for maintaining TSC stemness during expansion in vitro, thus improving their regenerative potential for cell-based therapy. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0306-3) contains supplementary material, which is available to authorized users.
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Epigenetic Regulation of Epidermal Stem Cell Biomarkers and Their Role in Wound Healing. Int J Mol Sci 2015; 17:ijms17010016. [PMID: 26712738 PMCID: PMC4730263 DOI: 10.3390/ijms17010016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Revised: 12/11/2015] [Accepted: 12/16/2015] [Indexed: 12/11/2022] Open
Abstract
As an actively renewable tissue, changes in skin architecture are subjected to the regulation of stem cells that maintain the population of cells responsible for the formation of epidermal layers. Stems cells retain their self-renewal property and express biomarkers that are unique to this population. However, differential regulation of the biomarkers can initiate the pathway of terminal cell differentiation. Although, pockets of non-clarity in stem cell maintenance and differentiation in skin still exist, the influence of epigenetics in epidermal stem cell functions and differentiation in skin homeostasis and wound healing is clearly evident. The focus of this review is to discuss the epigenetic regulation of confirmed and probable epidermal stem cell biomarkers in epidermal stratification of normal skin and in diseased states. The role of epigenetics in wound healing, especially in diseased states of diabetes and cancer, will also be conveyed.
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33
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Epigenomic Reprogramming of Adult Cardiomyocyte-Derived Cardiac Progenitor Cells. Sci Rep 2015; 5:17686. [PMID: 26657817 PMCID: PMC4677315 DOI: 10.1038/srep17686] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 10/14/2015] [Indexed: 01/01/2023] Open
Abstract
It has been believed that mammalian adult cardiomyocytes (ACMs) are terminally-differentiated and are unable to proliferate. Recently, using a bi-transgenic ACM fate mapping mouse model and an in vitro culture system, we demonstrated that adult mouse cardiomyocytes were able to dedifferentiate into cardiac progenitor-like cells (CPCs). However, little is known about the molecular basis of their intrinsic cellular plasticity. Here we integrate single-cell transcriptome and whole-genome DNA methylation analyses to unravel the molecular mechanisms underlying the dedifferentiation and cell cycle reentry of mouse ACMs. Compared to parental cardiomyocytes, dedifferentiated mouse cardiomyocyte-derived CPCs (mCPCs) display epigenomic reprogramming with many differentially-methylated regions, both hypermethylated and hypomethylated, across the entire genome. Correlated well with the methylome, our transcriptomic data showed that the genes encoding cardiac structure and function proteins are remarkably down-regulated in mCPCs, while those for cell cycle, proliferation, and stemness are significantly up-regulated. In addition, implantation of mCPCs into infarcted mouse myocardium improves cardiac function with augmented left ventricular ejection fraction. Our study demonstrates that the cellular plasticity of mammalian cardiomyocytes is the result of a well-orchestrated epigenomic reprogramming and a subsequent global transcriptomic alteration.
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Boonsanay V, Zhang T, Georgieva A, Kostin S, Qi H, Yuan X, Zhou Y, Braun T. Regulation of Skeletal Muscle Stem Cell Quiescence by Suv4-20h1-Dependent Facultative Heterochromatin Formation. Cell Stem Cell 2015; 18:229-42. [PMID: 26669898 DOI: 10.1016/j.stem.2015.11.002] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 10/08/2015] [Accepted: 11/05/2015] [Indexed: 12/16/2022]
Abstract
Skeletal muscle stem cells (MuSCs) are required for regeneration of adult muscle following injury, a response that demands activation of mainly quiescent MuSCs. Despite the need for dynamic regulation of MuSC quiescence, relatively little is known about the determinants of this property. Here, we show that Suv4-20h1, an H4K20 dimethyltransferase, controls MuSC quiescence by promoting formation of facultative heterochromatin (fHC). Deletion of Suv4-20h1 reduces fHC and induces transcriptional activation and repositioning of the MyoD locus away from the heterochromatic nuclear periphery. These effects promote MuSC activation, resulting in stem cell depletion and impaired long-term muscle regeneration. Genetic reduction of MyoD expression rescues fHC formation and lost MuSC quiescence, restoring muscle regeneration capacity in Suv4-20h1 mutants. Together, these findings reveal that Suv4-20h1 actively regulates MuSC quiescence via fHC formation and control of the MyoD locus, thereby guarding and preserving the stem cell pool over a lifetime.
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Affiliation(s)
- Verawan Boonsanay
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Ting Zhang
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Angelina Georgieva
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Sawa Kostin
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Hui Qi
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Xuejun Yuan
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany
| | - Yonggang Zhou
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany.
| | - Thomas Braun
- Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling, 61231 Bad Nauheim, Germany; Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, C1425FQD Buenos Aires, Argentina.
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35
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Luo M, Brooks M, Wicha MS. Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance. Curr Pharm Des 2015; 21:1301-10. [PMID: 25506895 DOI: 10.2174/1381612821666141211120604] [Citation(s) in RCA: 163] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 12/05/2014] [Indexed: 12/26/2022]
Abstract
Over the past several decades the traditional view of cancer being a homogeneous mass of rapid proliferating malignant cells is being replaced by a model of ever increasing complexity, which points out that cancers are complex tissues composed of multiple cell types. A large variety of immune and other host cells constitute the tumor microenvironment, which supports the growth and progression of the tumor where individual cancer cells evolve with increasing phenotypic and genetic heterogeneity. Furthermore, it has also become clear that, in addition to this cellular and genetic heterogeneity, most tumors exhibit a hierarchical organization composed of tumor cells displaying divergent lineage markers and at the apex of this hierarchy are cells capable of self-renewal. These "cancer stem cells" not only drive tumor growth, but also mediate metastasis and contribute to treatment resistance. Besides displaying remarkable genetic and phenotypic heterogeneity, cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states in a process regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in the process of tumor metastasis. In this review, we will discuss emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis. We also discuss the implications of these findings for the development of cancer stem cell targeted therapeutics.
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Affiliation(s)
| | | | - Max S Wicha
- University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109.
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The Epigenetic Reprogramming Roadmap in Generation of iPSCs from Somatic Cells. J Genet Genomics 2015; 42:661-70. [PMID: 26743984 DOI: 10.1016/j.jgg.2015.10.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 10/09/2015] [Accepted: 10/15/2015] [Indexed: 12/30/2022]
Abstract
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, which subsequently affects iPSC reprogramming, pluripotency, and differentiation capacity. Here, we review the epigenetic changes with a focus on histone modification (methylation and acetylation) and DNA modification (methylation) during iPSC induction. We look at changes in specific epigenetic signatures, aberrations and epigenetic memory during reprogramming and small molecules influencing the epigenetic reprogramming of somatic cells. Finally, we discuss how to improve iPSC generation and pluripotency through epigenetic manipulations.
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Association analysis between the distributions of histone modifications and gene expression in the human embryonic stem cell. Gene 2015; 575:90-100. [PMID: 26302750 DOI: 10.1016/j.gene.2015.08.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 05/13/2015] [Accepted: 08/20/2015] [Indexed: 12/17/2022]
Abstract
It is well known that histone modifications are associated with gene expression. In order to further study this relationship, 16 kinds of Chip-seq histone modification data and mRNA-seq data of the human embryonic stem cell H1 are chosen. The distributions of histone modifications in the regions flanking transcription start sites (TSSs) for highly expressed and lowly expressed genes are computed, respectively. And four types of distributions of histone modifications in regions flanking TSSs and the spatial patterning of the correlations between histone modifications and gene expression are detected. Our results suggest that the correlations between the regions overlapped by peaks are higher than the non-overlapped ones for each histone modification. In addition, to obtain the effect of the cooperative action of histone modification on gene expression, five histone modification clusters are found in highly expressed and lowly expressed genes, histone modification and gene expression interaction network is constructed. To further explore which region is the main target region for the specific histone modification, the human genes are divided into five functional regions. The results indicate that histone modifications are mostly located in the promoters of highly expressed genes versus the exons of lowly expressed genes, and exons have a smaller range of normalized tag counts than other gene elements in the two groups of genes. Finally, the type specificity and regional bias of histone modifications for 11 key transcription factor genes regulating the stem cell renewal are analyzed.
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Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5. PLoS One 2015; 10:e0125384. [PMID: 26047103 PMCID: PMC4457652 DOI: 10.1371/journal.pone.0125384] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/23/2015] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)-a co-activator not only for serum response factor, but also for Gata4 and Tbx5-is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (α-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up-regulated and all five proteins tested were visualized. IN SUMMARY (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate.
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Cardiac aging - Getting to the stem of the problem. J Mol Cell Cardiol 2015; 83:32-6. [PMID: 25886698 DOI: 10.1016/j.yjmcc.2015.04.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/20/2015] [Accepted: 04/08/2015] [Indexed: 01/08/2023]
Abstract
Cardiac aging is a heterogeneous process caused by a combination of stochastic events which manifests as loss of structure and function in the heart, however several recent studies draw attention to aging being primarily a stem cell problem. This review summarizes findings in support of the "stem cell hypothesis of aging" and discusses the impact of age on cardiac stem cells and the niche. This article is part of a Special Issue entitled 'CV Aging'.
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40
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Li T, Shi Y, Wang P, Guachalla LM, Sun B, Joerss T, Chen YS, Groth M, Krueger A, Platzer M, Yang YG, Rudolph KL, Wang ZQ. Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. EMBO J 2015; 34:1630-47. [PMID: 25770585 PMCID: PMC4475398 DOI: 10.15252/embj.201489947] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Accepted: 02/18/2015] [Indexed: 12/12/2022] Open
Abstract
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.
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Affiliation(s)
- Tangliang Li
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Yue Shi
- Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Pei Wang
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Luis Miguel Guachalla
- Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany
| | - Baofa Sun
- Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Tjard Joerss
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Yu-Sheng Chen
- Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Marco Groth
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Anja Krueger
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Matthias Platzer
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Yun-Gui Yang
- Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Karl Lenhard Rudolph
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany
| | - Zhao-Qi Wang
- Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany Faculty of Biology and Pharmacy, Friedrich-Schiller University of Jena, Jena, Germany
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Sekar TV, Foygel K, Devulapally R, Paulmurugan R. Degron protease blockade sensor to image epigenetic histone protein methylation in cells and living animals. ACS Chem Biol 2015; 10:165-74. [PMID: 25489787 PMCID: PMC4301175 DOI: 10.1021/cb5008037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
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Lysine
methylation of histone H3 and H4 has been identified as
a promising therapeutic target in treating various cellular diseases.
The availability of an in vivo assay that enables
rapid screening and preclinical evaluation of drugs that potentially
target this cellular process will significantly expedite the pace
of drug development. This study is the first to report the development
of a real-time molecular imaging biosensor (a fusion protein, [FLuc2]-[Suv39h1]-[(G4S)3]-[H3-K9]-[cODC]) that can detect and monitor the methylation
status of a specific histone lysine methylation mark (H3-K9) in live
animals. The sensitivity of this sensor was assessed in various cell
lines, in response to down-regulation of methyltransferase EHMT2 by
specific siRNA, and in nude mice with lysine replacement mutants. In vivo imaging in response to a combination of methyltransferase
inhibitors BIX01294 and Chaetocin in mice reveals the potential of
this sensor for preclinical drug evaluation. This biosensor thus has
demonstrated its utility in the detection of H3-K9 methylations in vivo and potential value in preclinical drug development.
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Affiliation(s)
- Thillai V. Sekar
- Molecular Imaging Program
at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States
| | - Kira Foygel
- Molecular Imaging Program
at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States
| | - Rammohan Devulapally
- Molecular Imaging Program
at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States
| | - Ramasamy Paulmurugan
- Molecular Imaging Program
at Stanford, Bio-X Program, Stanford University School of Medicine, Stanford, California, United States
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Schamberger AC, Mise N, Meiners S, Eickelberg O. Epigenetic mechanisms in COPD: implications for pathogenesis and drug discovery. Expert Opin Drug Discov 2015; 9:609-28. [PMID: 24850530 DOI: 10.1517/17460441.2014.913020] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The growing burden of COPD is due to continuous tobacco use, which is the most important risk factor of the disease, indoor fumes, occupational exposures and also aging of the world's population. Epigenetic mechanisms significantly contribute to COPD pathophysiology. AREAS COVERED This review focuses on disease-relevant changes in DNA modification, histone modification and non-coding RNA expression in COPD, and provides insight into novel therapeutic approaches modulating epigenetic mechanisms. Recent findings revealed, among others, globally changed DNA methylation patterns, decreased levels of histone deacetylases and reduced microRNAs levels in COPD. The authors also discuss a potential role of the chromatin silencing Polycomb group of proteins in COPD. EXPERT OPINION COPD is a highly complex disease and therapy development is complicated by the fact that many smokers develop both COPD and lung cancer. Of interest, combination therapies involving DNA methyltransferase inhibitors and anti-inflammatory drugs provide a promising approach, as they might be therapeutic for both COPD and cancer. Although the field of epigenetic research has virtually exploded over the last 10 years, particular efforts are required to enhance our knowledge of the COPD epigenome in order to successfully establish epigenetic-based therapies for this widespread disease.
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Affiliation(s)
- Andrea C Schamberger
- Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, University Hospital and Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL) , Max-Lebsche-Platz 31, 81377 Munich , Germany
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Stubenvoll A, Rice M, Wietelmann A, Wheeler M, Braun T. Attenuation of Wnt/β-catenin activity reverses enhanced generation of cardiomyocytes and cardiac defects caused by the loss of emerin. Hum Mol Genet 2014; 24:802-13. [PMID: 25274778 DOI: 10.1093/hmg/ddu498] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Mutations in EMD, encoding emerin cause skeletal muscle and heart defects in patients with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) but the underlying mechanisms leading to cardiac defects are poorly understood. Here, we investigated the role of emerin in controlling cardiomyocyte proliferation and cardiac remodeling and explored its function in regulation of the Wnt/β-catenin pathway. We observed a remarkable increase of cardiomyocytes in emerin-null adult mice accompanied with decreased numbers of multinucleated cells. Depletion of emerin in mouse ES cell-derived cardiomyocytes by shRNA caused hyperactivation of Wnt/β-catenin signaling, increased proliferation and abrogated timely cardiac differentiation. Likewise, emerin-null mice exhibited increased Wnt/β-catenin signaling, cardiac dysfunction and perturbed hypertrophic remodeling following pressure overload. Pharmacological inhibition of β-catenin normalized proliferation and differentiation of ES cell-derived cardiomyocytes while inactivation of a single allele of β-catenin efficiently rescued cardiac dysfunction in emerin-null mice. We conclude that emerin constrains β-catenin signaling in the heart providing tight control of cardiomyocyte numbers. Enhanced Wnt/β-catenin signaling seems to contribute to cardiac defects observed in X-EDMD. Hence, therapeutic inhibition of Wnt/β-catenin signaling might be beneficial for X-EDMD patients.
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Affiliation(s)
- Alexander Stubenvoll
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim 61231, Germany
| | - Megan Rice
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim 61231, Germany
| | - Astrid Wietelmann
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim 61231, Germany
| | - Matthew Wheeler
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim 61231, Germany
| | - Thomas Braun
- Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, Bad Nauheim 61231, Germany
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Loscalzo J, Handy DE. Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series). Pulm Circ 2014; 4:169-74. [PMID: 25006435 DOI: 10.1086/675979] [Citation(s) in RCA: 122] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 12/10/2013] [Indexed: 12/13/2022] Open
Abstract
Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment.
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Affiliation(s)
- Joseph Loscalzo
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Diane E Handy
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Expression profiles of histone lysine demethylases during cardiomyocyte differentiation of mouse embryonic stem cells. Acta Pharmacol Sin 2014; 35:899-906. [PMID: 24989252 DOI: 10.1038/aps.2014.40] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 04/27/2014] [Indexed: 12/15/2022]
Abstract
AIM Histone lysine demethylases (KDMs) control the lineage commitments of stem cells. However, the KDMs involved in the determination of the cardiomyogenic lineage are not fully defined. The aim of this study was to investigate the expression profiles of KDMs during the cardiac differentiation of mouse embryonic stem cells (mESCs). METHODS An in vitro cardiac differentiation system of mESCs with Brachyury (a mesodermal specific marker) and Flk-1(+)/Cxcr4(+) (dual cell surface biomarkers) selection was used. The expression profiles of KDMs during differentiation were analyzed using Q-PCR. To understand the contributions of KDMs to cardiomyogenesis, the mESCs on differentiation d 3.5 were sorted by FACS into Brachyury(+) cells and Brachyury(-) cells, and mESCs on d 5.5 were sorted into Flk-1(+)/Cxcr4(+) and Flk-1(-)/Cxcr4(-) cells. RESULTS mESCs were differentiated into spontaneously beating cardiomyocytes that were visible in embryoid bodies (EBs) on d 7. On d 12-14, all EBs developed spontaneously beating cardiomyocytes. Among the 16 KDMs examined, the expression levels of Phf8, Jarid1a, Jhdm1d, Utx, and Jmjd3 were increased by nearly 2-6-fold on d 14 compared with those on d 0. Brachyury(+) cells showed higher expression levels of Jmjd3, Jmjd2a and Jhdm1d than Brachyury(-) cells. A higher level of Jmjd3 was detected in Flk-1(+)/Cxcr4(+) cells, whereas the level of Jmjd2c was lower in both Brachyury(+) cells and Flk-1(+)/Cxcr4(+) cells. CONCLUSION KDMs may play important roles during cardiomyogenesis of mESCs. Our results provide a clue for further exploring the roles of KDMs in the cardiac lineage commitment of mESCs and the potential interference of cardiomyogenesis.
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McGinley AL, Li Y, Deliu Z, Wang QT. Additional sex combs-likefamily genes are required for normal cardiovascular development. Genesis 2014; 52:671-86. [DOI: 10.1002/dvg.22793] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 05/14/2014] [Accepted: 05/20/2014] [Indexed: 01/23/2023]
Affiliation(s)
- Andrea L. McGinley
- Department of Biological Sciences; University of Illinois at Chicago; Chicago Illinois
| | - Yanyang Li
- Department of Biological Sciences; University of Illinois at Chicago; Chicago Illinois
| | - Zane Deliu
- Department of Biological Sciences; University of Illinois at Chicago; Chicago Illinois
| | - Q. Tian Wang
- Department of Biological Sciences; University of Illinois at Chicago; Chicago Illinois
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Bevilacqua A, Willis MS, Bultman SJ. SWI/SNF chromatin-remodeling complexes in cardiovascular development and disease. Cardiovasc Pathol 2014; 23:85-91. [PMID: 24183004 PMCID: PMC3946279 DOI: 10.1016/j.carpath.2013.09.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 09/24/2013] [Accepted: 09/25/2013] [Indexed: 12/19/2022] Open
Abstract
Our understanding of congenital heart defects has been recently advanced by whole exome sequencing projects, which have identified de novo mutations in many genes encoding epigenetic regulators. Notably, multiple subunits of switching defective/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes have been identified as strong candidates underlying these defects because they physically and functionally interact with cardiogenic transcription factors critical to cardiac development, such as TBX5, GATA-4, and NKX2-5. While these studies indicate a critical role of SWI/SNF complexes in cardiac development and congenital heart disease, many exciting new discoveries have identified their critical role in the adult heart in both physiological and pathological conditions involving multiple cell types in the heart, including cardiomyocytes, vascular endothelial cells, pericytes, and neural crest cells. This review summarizes the role of SWI/SNF chromatin-remodeling complexes in cardiac development, congenital heart disease, cardiac hypertrophy, and vascular endothelial cell survival. Although the clinical relevance of SWI/SNF mutations has traditionally been focused primarily on their role in tumor suppression, these recent studies illustrate their critical role in the heart whereby they regulate cell proliferation, differentiation, and apoptosis of cardiac derived cell lines.
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Affiliation(s)
- Ariana Bevilacqua
- Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Monte S Willis
- Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
| | - Scott J Bultman
- Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA.
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48
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Recent advances in cardiovascular development. Circ Res 2013; 113:e102-5. [PMID: 24201114 DOI: 10.1161/circresaha.113.302820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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The Editors. Recent Developments in Cardiovascular Genetics. Circ Res 2013; 113:e88-91. [DOI: 10.1161/circresaha.113.302634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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50
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Potential benefits of cell therapy in coronary heart disease. J Cardiol 2013; 62:267-76. [PMID: 23834957 DOI: 10.1016/j.jjcc.2013.05.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 05/21/2013] [Accepted: 05/24/2013] [Indexed: 12/31/2022]
Abstract
Cardiovascular disease is the leading cause of morbidity and mortality in the world. In recent years, there has been an increasing interest both in basic and clinical research regarding the field of cell therapy for coronary heart disease (CHD). Several preclinical models of CHD have suggested that regenerative properties of stem and progenitor cells might help restoring myocardial functions in the event of cardiac diseases. Here, we summarize different types of stem/progenitor cells that have been tested in experimental and clinical settings of cardiac regeneration, from embryonic stem cells to induced pluripotent stem cells. Then, we provide a comprehensive description of the most common cell delivery strategies with their major pros and cons and underline the potential of tissue engineering and injectable matrices to address the crucial issue of restoring the three-dimensional structure of the injured myocardial region. Due to the encouraging results from preclinical models, the number of clinical trials with cell therapy is continuously increasing and includes patients with CHD and congestive heart failure. Most of the already published trials have demonstrated safety and feasibility of cell therapies in these clinical conditions. Several studies have also suggested that cell therapy results in improved clinical outcomes. Numerous ongoing clinical trials utilizing this therapy for CHD will address fundamental issues concerning cell source and population utilized, as well as the use of imaging techniques to assess cell homing and survival, all factors that affect the efficacy of different cell therapy strategies.
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