A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development

Paige, Sharon L.; Thomas, Sean; Stoick-Cooper, Cristi L.; Wang, Hao; Maves, Lisa; Sandstrom, Richard; Pabon, Lil; Reinecke, Hans; Pratt, Gabriel A.; Keller, Gordon; Moon, Randall T.; Stamatoyannopoulos, J; Murry, Charles E.

doi:10.1016/j.cell.2012.08.027

Cited by 312 publications

(380 citation statements)

References 44 publications

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“…Interestingly, these cardiac-specific TFs were previously found to have high levels of the repressive histone mark H3K27me3 in hESCs and many other non-cardiac lineages. However, during hESC differentiation towards hCM, the levels of H3K27me3 were decreased in hCM specific TFs, highlighting this mark as a major repressing factor in non-cardiac cell types (Paige et al, 2012;Xie et al, 2013). Whether DNA methylation offers a more stable regulation for cardiac-structural genes expression and whether the highly flexible nature of histone modifications is required for the dynamic cardiac-TF expression in a time-sensitive manner will be interesting questions to ask in future studies.…”

Section: Discussionmentioning

confidence: 97%

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

Liu

Plongthongkum³

et al. 2013

Protein Cell

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With defined culture protocol, human embryonic stem cells (hESCs) are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for cardiac disease therapies. In this study, we successfully generated a highly pure population of human cardiomyocytes (hCMs) (>95% cTnT + ) from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA methylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene functions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription factors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understanding of how the epigenetic machinery coordinates to regulate gene expression in different cell types.

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Section: Discussionmentioning

confidence: 97%

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

Liu

Plongthongkum³

et al. 2013

Protein Cell

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“…pluripotency > mesoderm > cardiac progenitors > cardiomyocytes) [56,57]. There is a progressive compaction of nucleic material during differentiation of ESCs [58] and also during cardiomyocyte maturation [59].…”

Section: Dynamic Changes In the Epigenome During Cardiomyocyte Differmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyoctes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigentic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury.

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“…Recently, by probing the temporal gene expression and chromatin changes during the directed differentiation of ESCs into cardiac lineages, several novel regulators of cardiac tissue formation have been identified [137,138]. This is achieved either by (1) determining the stage-specific activation of gene enhancers, and applying a DNA binding motif search to predict the transcription factors that are involved during cardiac differentiation [137]; or (2) by predicting key regulatory genes based on the induction of RNA expression, loss of repressive H3K27me3 marks and reciprocal increase of active H3K4me3 modification [138]. Therefore, it would be interesting to test if other novel tissue-specific regulators could be identified for different somatic lineages through analysis of temporal chromatin changes.…”

Section: Future Outlookmentioning

confidence: 99%

The transcriptional regulation of pluripotency

Yeo

2012

Cell Res

114

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Abbreviations: 2C (2-cell); 2i (two inhibitor); BMP4 (bone morphogenic protein 4); ChIP (chromatin immunoprecipitation); ChIP-seq (chromatin immunoprecipitation and sequencing); ESCs (embryonic stem cells); EpiSCs (Epiblast-derived stem cells); Fgf4 (fibroblast growth factor 4); hESCs (human embryonic stem cells); ICM (inner cell mass); iPSCs (induced pluripotent stem cells); LIF (leukemia inhibitory factor); lincRNA (large intergenic non-coding RNA); mESCs (mouse embryonic stem cells); miRNA (micro RNA); ncRNA (non-coding RNA); PcG (Polycomb group proteins); PGCs (primodial germ cells); POU (Pit-Oct-Unc); RNAi (RNA interference); RNA-seq (RNA sequencing); SCF (stem cell factor); siRNA (short interfering RNA); XaXa (double X-chromosome active); XaXi (single X-chromosome inactivated)The defining features of embryonic stem cells (ESCs) are their self-renewing and pluripotent capacities. Indeed, the ability to give rise into all cell types within the organism not only allows ESCs to function as an ideal in vitro tool to study embryonic development, but also offers great therapeutic potential within the field of regenerative medicine. However, it is also this same remarkable developmental plasticity that makes the efficient control of ESC differentiation into the desired cell type very difficult. Therefore, in order to harness ESCs for clinical applications, a detailed understanding of the molecular and cellular mechanisms controlling ESC pluripotency and lineage commitment is necessary. In this respect, through a variety of transcriptomic approaches, ESC pluripotency has been found to be regulated by a system of ESC-associated transcription factors; and the external signalling environment also acts as a key factor in modulating the ESC transcriptome. Here in this review, we summarize our current understanding of the transcriptional regulatory network in ESCs, discuss how the control of various signalling pathways could influence pluripotency, and provide a future outlook of ESC research.

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A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development

Cited by 312 publications

References 44 publications

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

Resetting the epigenome for heart regeneration.

The transcriptional regulation of pluripotency

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