Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs

Song, Yuelin; Berg, Patrick R. van den; Markoulaki, Styliani; Soldner, Frank; Dall’Agnese, Alessandra; Henninger, Jonathan E.; Drotar, Jesse; Rosenau, Nicholas A.; Cohen, Malkiel A.; Young, Richard A.; Semrau, Stefan; Stelzer, Yonatan; Jaenisch, Rudolf

doi:10.1016/j.molcel.2019.06.045

Cited by 80 publications

(66 citation statements)

References 78 publications

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“…Although we focused specifically at the actual TF binding sites in our analyses, all of the examples in this study show that the associations of TF binding and CpG methylation patterns across development still exists not just at the core binding site, but at the surrounding region as well. This is consistent with previous studies showing that knocking out two specific TF binding sites within a super enhancer results in increased de-novo DNA methylation of the entire super enhancer region [42]. Taken together, the evidence suggests that TF binding and placeholder nucleosome occupancy may be coupled, but further studies are needed to verify the existence of placeholder nucleosomes in mammals and the relationship of their localization to TF binding during PGC and pre-implantation development.…”

Section: Discussionsupporting

confidence: 91%

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

Kremsky

Corcés

2019

Preprint

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A growing body of evidence suggests that certain phenotypic traits of epigenetic origin can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and preimplantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global reprogramming, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germ line and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become demethylated during global de-methylation, and then become re-methylated. The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and preimplantation development by ensuring that the methylation status of CpGs is maintained after reprogramming of DNA methylation. Based on our findings, we propose a model in which transcription factor binding during the re-methylation phases of primordial germ cell and preimplantation development allow epigenetic information to be maintained trans-generationally even at sites where DNA methylation is lost during global de-methylation.

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Section: Discussionsupporting

confidence: 91%

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

Kremsky

Corcés

2019

Preprint

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“…ESCs in serum/LIF can toggle from naive-to-primed pluripotency states with some cells initiating differentiation, as reflected in heterogeneous transcriptional states 28,29 . Interestingly, cell state fluctuations also manifest at the epigenetic level with evidence of CpG methylation oscillations at enhancers [30][31][32][33] . To assess the level of cell-to-cell methylation heterogeneity at PU and DM, and its potential association with gene expression, we reanalysed parallel single-cell transcriptional (sc-RNA-seq) and bisulphite (sc-BS-seq) data from ESCs grown in serum/LIF and 2i/LIF 30 .…”

Section: Dm and Pu Units Regulate Distinct Pluripotency Gene Modulesmentioning

confidence: 99%

Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency

et al. 2020

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Clusters of enhancers, referred as to super-enhancers (SEs), control the expression of cell identity genes. The organisation of these clusters, and how they are remodelled upon developmental transitions remain poorly understood. Here, we report the existence of two types of enhancer units within SEs typified by distinctive CpG methylation dynamics in embryonic stem cells (ESCs). We find that these units are either prone for decommissioning or remain constitutively active in epiblast stem cells (EpiSCs), as further established in the peri-implantation epiblast in vivo. Mechanistically, we show a pivotal role for ESRRB in regulating the activity of ESC-specific enhancer units and propose that the developmentally regulated silencing of ESRRB triggers the selective inactivation of these units within SEs. Our study provides insights into the molecular events that follow the loss of ESRRB binding, and offers a mechanism by which the naive pluripotency transcriptional programme can be partially reset upon embryo implantation.

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“…While limitations in the current mouse genome assemblies prevented us from identifying the causal variant(s) encoded by the Dlk1-Dio3 QTL, we speculate that the relevant genes may facilitate the recruitment of the de novo DNA methylation machinery to susceptible gene loci. This appears to be a dynamic process, potentially resembling recent observations made at pluripotency-associated enhancers (Song et al, 2019), that can be counteracted by stimulating DNA and/or histone demethylases. The ability to suppress imprint instability by ascorbic acid may prove beneficial when attempting to preserve the developmental potential of pluripotent cell lines that have been determined to be susceptible to ICR hypermethylation due to their genetic composition.…”

Section: Discussionmentioning

confidence: 54%

A susceptibility locus on chromosome 13 profoundly impacts the stability of genomic imprinting in mouse pluripotent stem cells

Swanzey

McNamara

Apostolou³

et al. 2020

Preprint

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Cultured pluripotent cells accumulate detrimental epigenetic alterations, including DNA methylation changes at imprinted genes known as loss-of-imprinting (LOI). Despite the substantial biomedical relevance of this phenomenon, the molecular cause of this epigenetic instability in pluripotent cells remains unknown. While the occurrence of LOI is generally considered a stochastic phenomenon, here we document a strong genetic determinant that segregates mouse pluripotent cells into epigenetically stable and unstable cell lines. Unstable lines exhibit hypermethylation at Dlk1-Dio3 and select other imprinted loci, which is associated with impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and can preserve developmental potential.Susceptibility to LOI greatly differs between commonly used mouse strains, which we utilize to map a causal region on chromosome 13 with Quantitative Trait Locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific epigenetic abnormalities in pluripotent cells and provide a non-invasive way to suppress them. This highlights the importance of considering genetics in conjunction with culture conditions for assuring the quality of pluripotent cells for biomedical applications.

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Dynamic Enhancer DNA Methylation as Basis for Transcriptional and Cellular Heterogeneity of ESCs

Cited by 80 publications

References 78 publications

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

Transcription factors protect from DNA re-methylation during reprograming of primordial germ cells and pre-implantation embryos

Dynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency

A susceptibility locus on chromosome 13 profoundly impacts the stability of genomic imprinting in mouse pluripotent stem cells

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