Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells

Juan, Aster H.; Wang, Stan; Ko, Kyung Dae; Zare, Hossein; Tsai, Ping-Huei; Feng, Xuesong; Vivanco, Karinna O.; Ascoli, Anthony M.; Gutierrez-Cruz, Gustavo; Krebs, Jordan; Sidoli, Simone; Knight, Adam L.; Pedersen, Roger A.; Garcia, Benjamin A.; Casellas, Rafael; Zou, Jizhong; Sartorelli, Vittorio

doi:10.1016/j.celrep.2016.09.087

Cited by 80 publications

(61 citation statements)

References 66 publications

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“…This would fit to a model in which UTX/JMJD3 act relatively unspecific on H3K27me3 scattered across the genome, limiting it's abundance predominantly non-Polycomb targets. Such model is also in agreement with genome-wide maps of UTX/JMJD3 that found a relatively flat distribution with weak enrichment at active gene promoters rather than Polycomb targets 23,24 . Interestingly, GSK-J4 treatment assimilated H3K27me3 genome-wide distribution in serum and 2i almost completely ( Supplementary Figure 12b ).…”

Section: Active Demethylation Limits H3k27me3 Levels Genome-widesupporting

confidence: 88%

Quantitative multiplexed ChIP reveals global alterations that shape promoter bivalency in ground state embryonic stem cells

Kumar

ElsaÌˆsser

2019

Preprint

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To understand the epigenetic foundation of naïve pluripotent cells, we implement a quantitative multiplexed ChIP-Seq method (MINUTE-ChIP) comparing mouse ESC grown in 2i versus Serum conditions. Combined with quantitative western blot and mass spectrometry, we find compelling evidence for a broad H3K27me3 hypermethylation of the genome, concomitant with the widespread loss of DNA CpG methylation. We show that opposing action of EZH2 and JMJD3/UTX shape the H3K27me3 landscape, with almost all bivalent promoters stably retaining high H3K27me3 levels in 2i. In parallel, we show a mechanistically uncoupled, global decrease of H3K4me3 and strong reduction at bivalent promoters, suggesting that low H3K4me3 and high H3K27me3 levels at bivalent promoters safeguard naïve pluripotency.

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Section: Active Demethylation Limits H3k27me3 Levels Genome-widesupporting

confidence: 88%

Quantitative multiplexed ChIP reveals global alterations that shape promoter bivalency in ground state embryonic stem cells

Kumar

ElsaÌˆsser

2019

Preprint

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“…Approximately 56,000 Spt6 peaks were detected with the majority (~61%) of them being located at intragenic regions, ~ 20% at promoters, and ~18% at intergenic regions (Figure S1 and Figure 1A). To refine genomic locations, we intersected ChIP-seq maps for H3K4me3, H3K4me1, H3K27ac, and H3K27me3 (Juan et al, 2016) with Spt6 datasets. Spt6 peaks intersected with ~ 66% (21,657/32,746) H3K4me3 + , ~44% (30,697/69,649) H3K4me1 + , ~57% (25,535/44,845) H3K27ac + , and ~27% (9,046/33,272) H3K27me3 + regions (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Mock DNA (input DNA) was used against the matched sample data to call enriched regions and control for the false-positive detection rate (FDR). ChIP-seq data of H3K27me3, H3K27ac, H3K4me1, H3K4me3 in mouse ESCs were published in (Juan et al, 2016). ChIP-seq data of Med1, Oct4, Sox2, and Nanog in mouse ESC (Whyte et al, 2013) were downloaded and processed with the same settings.…”

Section: Star*methodsmentioning

confidence: 99%

The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins

Wang

Juan

et al. 2017

Molecular Cell

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SUMMARY Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation and mRNA processing. Here, we report that depleting Spt6 in ESCs reduced expression of pluripotency factors, increased expression of cell lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective down-regulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers where Spt6 controls histone H3K27 acetylation and methylation, and super-enhancer RNA transcription. In ESCs, Spt6 interacted with the PRC2 core subunit Suz12 and prevented H3K27me3 accumulation at ESC super-enhancers and associated promoters. Biochemical as well as functional experiments revealed that Spt6 could compete for binding of the PRC2 methyltransferase Ezh2 to Suz12 and reduce PRC2 chromatin engagement. Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions.

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“…This complex is recruited to and silences specific regions of the genome by transferring methyl groups onto lysine 27 of histone H3. This chromatin modification has well-defined roles in the maintenance of the stem cell state and genomic imprinting (Juan et al, 2016; Inoue et al, 2017). Collectively, these observations indicate that oxygen concentrations have a strong influence on the control of chromatin modifying enzymes and significantly impact the regulation of two crucial pluripotency-associated genes.…”

Section: Discussionmentioning

confidence: 99%

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

Skiles

Kester

Pryor

et al. 2018

Gene Expression Patterns

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Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a. These transcriptional changes were associated with alterations in the control of multiple imprinted genes, including H19, Igf2, Igf2r, and Peg3. Similarly, exposure of in vitro produced bovine embryos to atmospheric oxygen concentrations was associated with disruptions in the transcriptional regulation of TET1, TET3, and DNMT3a, along with the DNA methyltransferase co-factor HELLS. In addition, exposure to high oxygen was associated with alterations in the abundance of transcripts encoding members of the Polycomb repressor complex (EED and EZH2), the histone methyltransferase SETDB1 and multiple histone demethylases (KDM1A, KDM4B, and KDM4C). These disruptions were accompanied by a reduction in embryo viability and suppression of the pluripotency genes NANOG and SOX2. These experiments demonstrate that oxygen has the capacity to modulate the transcriptional control of chromatin modifying genes involved in the establishment and maintenance of both pluripotency and genomic imprinting.

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Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells

Cited by 80 publications

References 66 publications

Quantitative multiplexed ChIP reveals global alterations that shape promoter bivalency in ground state embryonic stem cells

Quantitative multiplexed ChIP reveals global alterations that shape promoter bivalency in ground state embryonic stem cells

The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

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