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Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs [BiSulfite-seq]

ABSTRACT: Variable levels of DNA methylation have been reported at tissue-specific differential methylation regions (DMRs) overlapping enhancers, including super-enhancers (SEs) associated with key cell identity genes, but the mechanisms responsible for this intriguing behavior are not well understood. We used allele-specific reporters at the endogenous Sox2 and miR290 super-enhancers (SE) in embryonic stem cells and found that the allelic DNA methylation state is dynamically switching, resulting in cell-to-cell heterogeneity. Dynamic DNA methylation is driven by the balance between DNA methyl-transferases and transcription factor binding on one side, and co-regulated with the Mediator complex recruitment and H3K27ac level changes at regulatory elements on the other side. DNA methylation at the Sox2 and the miR290 SEs is independently regulated and has distinct consequences on the cellular differentiation state. Dynamic allele-specific DNA methylation at the two SEs was also seen at different stages in preimplantation embryos, revealing that methylation heterogeneity occurs in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE132404 | GEO | 2019/06/15

REPOSITORIES: GEO

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Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs [RNA-seq]

Project description:Variable levels of DNA methylation have been reported at tissue-specific differential methylation regions (DMRs) overlapping enhancers, including super-enhancers (SEs) associated with key cell identity genes, but the mechanisms responsible for this intriguing behavior are not well understood. We used allele-specific reporters at the endogenous Sox2 and miR290 super-enhancers (SE) in embryonic stem cells and found that the allelic DNA methylation state is dynamically switching, resulting in cell-to-cell heterogeneity. Dynamic DNA methylation is driven by the balance between DNA methyl-transferases and transcription factor binding on one side, and co-regulated with the Mediator complex recruitment and H3K27ac level changes at regulatory elements on the other side. DNA methylation at the Sox2 and the miR290 SEs is independently regulated and has distinct consequences on the cellular differentiation state. Dynamic allele-specific DNA methylation at the two SEs was also seen at different stages in preimplantation embryos, revealing that methylation heterogeneity occurs in vivo.

2019-06-15 | GSE132414 | GEO

Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs [ChIP-seq]

2019-06-15 | GSE132376 | GEO

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity for Pluripotency and Reprogramming [ChIP-Seq]

Project description:Super-enhancers (SEs) are large clusters of transcriptional enhancers that are co-occupied by multiple lineage specific transcription factors driving expression of genes that define cell identity. In embryonic stem cells (ESCs), SEs are highly enriched for Oct4, Sox2, and Nanog in the enhanceosome assembly and express enhancer RNAs (eRNAs). We sought to dissect the molecular control mechanism of SE activity and eRNA transcription for pluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, a key pluripotency and reprogramming factor that guides the ESC-specific enhanceosome assembly and orchestrates the hierarchical transcriptional activation during the final stage of reprogramming, we discovered Tex10 as a novel pluripotency factor that is evolutionally conserved and functionally significant in ESC self-renewal, early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent manner and coordinates histone acetylation and DNA demethylation of SEs. Our study sheds new light on epigenetic control of SE activity for cell fate determination. Genome binding/occupancy profiling of Tex10 was performed in mouse embryonic stem cells by ChIP sequencing.

2015-05-07 | E-GEOD-66735 | biostudies-arrayexpress

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity for Pluripotency and Reprogramming [RNA-Seq]

Project description:Super-enhancers (SEs) are large clusters of transcriptional enhancers that are co-occupied by multiple lineage specific transcription factors driving expression of genes that define cell identity. In embryonic stem cells (ESCs), SEs are highly enriched for Oct4, Sox2, and Nanog in the enhanceosome assembly and express enhancer RNAs (eRNAs). We sought to dissect the molecular control mechanism of SE activity and eRNA transcription for pluripotency and reprogramming. Starting from a protein interaction network surrounding Sox2, a key pluripotency and reprogramming factor that guides the ESC-specific enhanceosome assembly and orchestrates the hierarchical transcriptional activation during the final stage of reprogramming, we discovered Tex10 as a novel pluripotency factor that is evolutionally conserved and functionally significant in ESC self-renewal, early embryo development, and reprogramming. Tex10 is enriched at SEs in a Sox2-dependent manner and coordinates histone acetylation and DNA demethylation of SEs. Our study sheds new light on epigenetic control of SE activity for cell fate determination. RNA sequencing analysis was performed in mouse embryonic stem cells with Luciferase and Tex10 knockdown. RNA-seq Experiments were carry out in two biological replicates.

2015-05-07 | E-GEOD-66734 | biostudies-arrayexpress

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity for Pluripotency and Reprogramming [ChIP-Seq]

2015-05-07 | GSE66735 | GEO

Tex10 Coordinates Epigenetic Control of Super-Enhancer Activity for Pluripotency and Reprogramming [RNA-Seq]

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Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers

Project description:Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here we show that super-enhancers consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. ChIP-Seq for H3K27ac and RNA Pol II in mouse embryonic stem cells with CRISPR-deleted enhancers

2014-12-15 | E-GEOD-64188 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [ChIP-Seq]

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form “super-enhancers” at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. ChIP-Seq and controls associated with Super-Enhancers in murine cell types

2013-02-13 | E-GEOD-44286 | biostudies-arrayexpress

Deconstruction of DNA methylation patterns during myogenesis reveals specific epigenetic events in the establishment of the skeletal muscle lineage

Project description:Cellular differentiation involves widespread epigenetic reprogramming, including modulation of DNA methylation patterns. We have investigated DNA genome-wide methylation dynamics in embryonic stem cells, primary myoblasts, terminal differentiated myotubes and mature myofibers. About 1.000 differentially methylated regions (DMRs) have been indentified during muscle-lineage determination and terminal differentiation. As a whole, muscle lineage commitment was characterized by a major gain of DNA methylation, while muscle differentiation was accompanied by loss of DNA methylation in CpG-poor regions. Notably, hypomethylated regions in muscle cells were neighboured by enhancer-type chromatin, suggesting the involvement of DNA methylation in the regulation of cell-type specific enhancers. Indeed, one of the hypomethylations detected in muscle cells affected the super-enhancer of the master transcription factor Myf5. Super-enhancers have been defined as large clusters of transcriptional enhancers driving cell-identity and gene expression, but how these lineage-specific super-enhancers are specifically activated or repressed in different tissues is not well understood. We demonstrated that the binding of the transcription factor USF1 to Myf5 locus occurs upon DNA demethylation of the super-enhancer region in myogenic committed cells. Taken all together, we have characterized the unique DNA methylation signatures of muscle-committed cells and highlighted the importance of DNA methylation mediated regulation of cell identity super-enhancers. We have investigated DNA genome-wide methylation dynamics in embryonic stem cells, primary myoblasts, terminal differentiated myotubes and mature myofibers by AIMS-seq techniques and coupled to microarray expression data by SurePrint G3 Mouse 8x60K from Agilent Technologies. Samples were in triplicates, except for ESCs (quadruplicates).

2015-01-16 | E-GEOD-65037 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [gene expression]

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form M-bM-^@M-^\super-enhancersM-bM-^@M-^] at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. Time-course of gene expression following shRNA knockdown of Oct4 and Med12.

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