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

Gu, Ying; Liu, Guanghui; Plongthongkum, Nongluk; Benner, Chris; Yi, Fei; Qu, Jing; Suzuki, Keiichiro; Yang, Jiping; Zhang, Weiqi; Li, Mo; Montserrat, Núria; Crespo, Isaac; Sol, Antonio del; Esteban, Concepción Rodrı́guez; Zhang, Kun; Belmonte, Juan Carlos Izpisúa

doi:10.1007/s13238-013-3911-2

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…In contrast, our results indicate that amniocyte DNA methylation and gene expression only weakly correlate, and when common functional groups or pathways are analyzed separately, the relationships can be positive, negative or uncorrelated, implying diverse mechanisms regulate different types of genes. In line with our bioinformatics analyses, one previous study documented markedly different DNA methylation patterns for cardiac structural genes compared with cardiac-specific transcription factors (Gu et al, 2014). We propose that these two cardiomyocyte-specific gene categories (e.g.…”

Section: Discussionsupporting

confidence: 88%

Deriving Cardiomyocytes from Human Amniocytes

Sunderland

Demarest

et al. 2018

Preprint

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STATEMENTAmniocytes are a possible source of patient-specific cardiomyocytes for newborns with congenital heart disease. Genome-wide DNA methylation patterns and transcriptional repressors preclude direct differentiation, but pluripotent reprogramming provides cardiomyocytes for dissecting genetic pathways contributing to this disease. ABSTRACTMany forms of congenital heart disease (CHD) have high morbidity-mortality rates and require challenging surgeries. Human amniocytes have important stem cell characteristics and could potentially provide patient-specific tissue for repairs of some types of CHDs. We report that amniocytes express features of poised cardiomyocytes. However, a variety of direct reprogramming approaches failed to convert their fetal and transcriptionally repressed state into bona fide cardiomyocytes. Induced-pluripotent stem cell (iPSC) reprogramming removes repression and converts amniocytes to a baseline pluripotent state. Based on molecular and electrophysiological signatures, iPSC reprogrammed amniocytes can be induced to differentiate into functionally immature, predominantly ventricular cardiomyocytes and a heterogeneous mixture of vascular and unspecified epithelial cells. Developmental time course analyses and pattern clustering of amniocyte-derived cardiomyocytes identifies numerous temporal coregulators of cardiac induction and maturation as well as distinct sarcomeric and ion channel gene signatures. Normal fetal cardiomyocytes are derived by overcoming complex forms of transcriptional repression that suppress direct transdifferentiation of human amniocytes. These results suggest the possibility of using amniocytes as a source of patient-specific ventricular cardiomyocytes for cell therapies.

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Section: Discussionsupporting

confidence: 88%

Deriving Cardiomyocytes from Human Amniocytes

Sunderland

Demarest

et al. 2018

Preprint

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“…CM differentiation from pluripotent cell sources has already significantly improved our understanding of transcriptional and epigenetic programs involved in human cardiomyogenesis (Bar-Nur et al, 2011;Kattman et al, 2011;Rajala et al, 2011;Paige et al, 2012;Xu et al, 2012;Zwi-Dantsis and Gepstein, 2012;Chow et al, 2013a;Lian et al, 2013;Gu et al, 2014). Extensions of findings from transcriptional studies have resulted in major improvements in CM yield by recapitulation/enhancement of normal differentiation programs (Kattman et al, 2011;Rai et al, 2012;Lian et al, 2013), but what role do epigenetic and epigenomic studies play?…”

Section: Generation and Enrichment Of Pluripotent-cmsmentioning

confidence: 99%

“…Additional studies on bivalent histone marks through CM differentiation have shown that CMs electrophysiology is epigenetically regulated through H3K27me3 and H3K4me3 dynamics and that derived CMs may be primed epigenetically for further maturation (Chow et al, 2013b). Pair-wise promoter DNA methylation studies on hESCs and CMs have shown that DNA hypomethylation also occurs at structural genes during cardiomyogenesis (Gu et al, 2014). In our laboratory, recent work has confirmed CM structural gene promoter hypomethylation, which appears to be progressive over multiple stages of differentiation (manuscript in preparation).…”

Section: Epigenetics Of Pluripotent-cm Differentiationmentioning

confidence: 99%

An epigenetic perspective on the failing heart and pluripotent-derived-cardiomyocytes for cell replacement therapy

Tompkins

Riggs

2014

Front. Biol.

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As life expectancy rises, the prevalence of heart failure is steadily increasing, while donors for organ transplantation remain in short supply (Zwi-Dantsis and Gepstein, 2012). Indeed, myocardial infarction represents the foremost cause of death within industrialized nations (Henning, 2011) and further, approximately 1% of all newborns harbor a congenital heart defect. Although medical interventions allow > 80% of those with cardiac defects to survive to adulthood, there are often extreme emotional and financial burdens that accompany such congenital anomalies, and many individuals will remain at a heightened risk for myocardial infarction throughout the remainder of their lives (Verheugt et al., 2010;Amianto et al., 2011). In this review, we will discuss the nature of the failing heart and strategies for repair from an epigenetic standpoint. Significant focus will reside on pluripotent-to-cardiomyocyte differentiation for cell replacement, epigenetic mechanisms of cardiomyocyte differentiation, epigenetic "memories," and epigenetic control of cardiomyocyte cell fate toward translational utility.

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“…During the early stage of embryonic development, CpG islands maintain unmethylated states in which the majority of genes undergo active demethylation, and obtain DNA methylation patterns specific to certain tissue types and developmental stages [19]. Some studies have detected increases in DNA methylation-mediated epigenetic repression during cardiomyocyte lineage specification or decreases during neurogenesis from ESCs [20,21]. However, in our study, hypomethylation events occurred more often than hypermethylation events upon erythroid differentiation from hESCs, which is in agreement with events during mouse erythropoiesis and the results of study investigating CD34…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

Liu

Feng²,

Sun

et al. 2017

Epigenomics

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Aim:To investigate the role of DNA methylation during erythrocyte production by human embryonic stem cells (hESCs). Methods: We employed an erythroid differentiation model from hESCs, and then tracked the genome-wide DNA methylation maps and gene expression patterns through an Infinium HumanMethylation450K BeadChip and an Ilumina Human HT-12 v4 Expression Beadchip, respectively. Results: A negative correlation between DNA methylation and gene expression was substantially enriched during the later differentiation stage and was present in both the promoter and the gene body. Moreover, erythropoietic genes with differentially methylated CpG sites that were primarily enriched in nonisland regions were upregulated, and demethylation of their gene bodies was associated with the presence of enhancers and DNase I hypersensitive sites. Finally, the components of JAK-STAT-NF-κB signaling were DNA hypomethylated and upregulated, which targets the key genes for erythropoiesis. Conclusion: Erythroid lineage commitment by hESCs requires genome-wide DNA methylation modifications to remodel gene expression dynamics. Erythrocyte transfusion is useful for many patients with hematological disorders or emergencies. As erythrocyte supply depends on limited voluntary donations and involves the risk of infectious disease transmission, human embryonic stem cells (hESCs) are ideal candidates for in vitro erythropoiesis due to their nonimmunoreactive nature and limitless quantities [1][2][3]. However, many technical obstacles must be overcome to achieve single-lineage differentiation. Thus, understanding the mechanisms governing pluripotent stem cell erythropoiesis is highly important.DNA methylation at CpG dinucleotide, which constitutes the most important epigenetic modification, regulates the gene expression dynamics of transcription factors during erythropoiesis [4]. However, the role of total-genome DNA methylation in determining stem cell fate and erythroid-lineage commitment remains poorly understood. Employing large-scale DNA methylation mapping, some in vivo studies have uncovered the changes in DNA methylation during hematopoietic stem cell (HSC) or hematopoietic progenitor cell differentiation and lineage commitment [4][5][6][7], and in vitro studies have revealed hypomethylation events that occur during erythropoiesis [4,8], although some studies directly comparing differentiated cell types have detected virtually no demethylation during cellular differentiation, indicating increased DNA methylation-mediated epigenetic repression during lineage specification [9,10]. Therefore, hypomethylation may be more significant for erythropoiesis than the development of other cell type. Moreover, according to a recent study, methylation is most relevant at the HSC level but less so after

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

Cited by 7 publications

References 23 publications

Deriving Cardiomyocytes from Human Amniocytes

Deriving Cardiomyocytes from Human Amniocytes

An epigenetic perspective on the failing heart and pluripotent-derived-cardiomyocytes for cell replacement therapy

Genome-Wide Dna Methylation Drives Human Embryonic Stem Cell Erythropoiesis by Remodeling Gene Expression Dynamics

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