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DNA-binding pluripotency factors and DNA demethylases can cooperate to maintain pluripotent stem cell identity even in the absence of Brd4 [RNA-seq]

ABSTRACT: Histone acetylation and the acetyl-lysine reader Brd4 have recently been implicated in embryonic stem cell (ESC) proliferation and self-renewal. We found that naïve pluripotent ESCs exhibit increased incorporation of glucose-derived carbons onto acetylated histones and elevations in H3K9ac and Brd4 recruitment at pluripotency gene promoters. Surprisingly, both H3K9 acetyltransferases, GCN5 and PCAF, and Brd4 recruitment were dispensable for proliferation, self-renewal and pluripotency of naïve ESCs. Naïve ESCs maintain gene expression by stabilizing Mediator at core pluripotency genes in a Brd4-independent manner. Brd4-independent proliferation could also be achieved in metastable ESCs by overexpression of pluripotency transcription factors. Under all conditions, self-renewal required the DNA methylcytosine oxidases Tet1 and Tet2. These data reveal that there is minimal dependence on Brd4 for self-renewal of naïve ESCs. Instead, the relative levels of DNA methylation and transcription factor abundance determine the requirement for bromodomain recognition of histone acetylation to the maintenance of stem cell identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE88760 | GEO | 2018/04/10

REPOSITORIES: GEO

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Transcription factors and Tet1/2 enable Brd4-independent maintenance of stem cell identity

Project description:Histone acetylation and the acetyl-lysine reader Brd4 have recently been implicated in embryonic stem cell (ESC) proliferation and self-renewal. We found that na•ve pluripotent ESCs exhibit increased incorporation of glucose-derived carbons onto acetylated histones and elevations in H3K9ac and Brd4 recruitment at pluripotency gene promoters. Surprisingly, both H3K9 acetyltransferases, GCN5 and PCAF, and Brd4 recruitment were dispensable for proliferation, self-renewal and pluripotency of na•ve ESCs. Na•ve ESCs maintain gene expression by stabilizing Mediator at core pluripotency genes in a Brd4-independent manner. Brd4-independent proliferation could also be achieved in metastable ESCs by overexpression of pluripotency transcription factors. Under all conditions, self-renewal required the DNA methylcytosine oxidases Tet1 and Tet2. These data reveal that there is minimal dependence on Brd4 for self-renewal of na•ve ESCs. Instead, the relative levels of DNA methylation and transcription factor abundance determine the requirement for bromodomain recognition of histone acetylation to the maintenance of stem cell identity.

2018-04-09 | GSE88769 | GEO

DNA-binding pluripotency factors and DNA demethylases can cooperate to maintain pluripotent stem cell identity even in the absence of Brd4 [ATAC-seq]

Project description:The relative contributions of sequence-specific transcription factors and DNA/histone modifications to stem cell maintenance remains controversial. For example, the acetyllysine reader Brd4 has been implicated in stem cell maintenance, but how absolute the role of Brd4 is in maintaining pluripotency remains unclear. Here we show that Brd4 is dispensable for the proliferation, self-renewal and pluripotency of embryonic stem cells. In naive, ground state pluripotent stem cells, Mediator recruitment and transcription factor binding to stem cell-specific genes are maintained in the absence of Brd4 function or expression. Even in metastable embryonic stem cells poised for differentiation, Brd4 independence can be maintained by overexpression of pluripotency transcription factors so long as the DNA methylcytosine oxidases, Tet1 and Tet2, are present to facilitate chromatin accessibility. These data reveal that Brd4 is not essential for self-renewal of embryonic stem cells. Rather, Brd4 contributes to stem cell maintenance only under conditions where the expression of pluripotency transcription factors and/or DNA demethylation machinery is compromised.

2018-04-09 | GSE95641 | GEO

A balanced Oct4 protein interaction network is crucial for maintaining pluripotency

Project description:Oct4 is considered a master transcription factor for pluripotent cell self-renewal and embryo development. It primarily collaborates with other transcriptional factors or coregulators to maintain pluripotency. However, it is still unclear how Oct4 interacts with its partners. Here, we show that the Oct4 linker interface mediates competing and balanced Oct4 protein interactions which are crucial for maintaining pluripotency. Linker mutant ESCs maintain the key pluripotency genes expression, but show decreased expression of self-renewal genes and increased expression of differentiation genes which result in impaired ESCs self-renewal and early embryonic lethality. Linker mutation dose not affect Oct4 genomic binding and transactivation potential, but breaks the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 was decreased, but interactions between Oct4 and Cbx1, Ctr9, Cdc73 were increased which disrupt the epigenetic state of ESCs. Overexpression of Klf5 or knockdown Cbx1, Cdc73 rescue the cellular phenotype of linker mutant ESCs by rebalancing Oct4 interactome indicating that different partners interact with Oct4 competitively. Thus, by showing how Oct4 interacts with different partners, we provide novel molecular insights to explain how Oct4 contributes to the maintenance of pluripotency.

2021-12-10 | PXD017456 | Pride

DNMTs Play an Important Role in Maintaining the Pluripotency of Leukemia Inhibitory Factor Dependent Embryonic Stem Cells

Project description:Naïve pluripotency can be maintained in 2i/LIF supplements, which primarily affect canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is sufficient to maintain naïve self-renewal remain unclear. Here we show that LIF alone medium is sufficient for adaptation of 2i/L-ESCs to ESCs with hypermethylated state (L-ESCs). Global transcriptomic analysis show that L-ESCs are close to 2i/L-ESCs and in a stable state between naïve and primed pluripotency. Notably, our results demonstrate that DNA methyltransferases (DNMTs) play an important role for LIF-dependent mouse ESCs adaptation and self-renew. LIF-dependent ESCs adaptation efficiency is significantly increased in serum treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike epiblast stem cells, L-ESCs contribute to somatic tissues and germ cells in chimaeras. L-ESCs cultured in such a simple conditions in this study would provide a more conducive platform to clarify the molecular mechanism of ESCs in vitro culture.

2021-01-25 | GSE142799 | GEO

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation [Microarray]

Project description:Self-renewal of embryonic stem cells (ESCs) cultured in serum-LIF is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here we purify ESCs with distinct TF expression levels from serum-LIF cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in NANOGlow cells. Independent Esrrb reporter lines demonstrate that ESRRBnegative ESCs cannot effectively self-renew. Upon ESRRB loss, pre-implantation pluripotency gene expression collapses. ChIP-Seq identifies different regulatory element classes that bind both OCT4 and NANOG in ESRRBhigh cells. Class I elements lose NANOG and OCT4 binding in ESRRBnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, class II elements retain OCT4 but not NANOG binding in ESRRBnegative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

2018-09-13 | GSE118906 | GEO

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation [ChIP-seq]

2018-09-13 | GSE118905 | GEO

Mus musculus

Project description:Converting self-renewal in naïve pluripotency to naïve endoderm [I]

| PRJNA311547 | ENA

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [RNA-seq]

Project description:Mouse embryonic stem cells (ESCs) cultured with inhibitors of MEK and GSK3 (2iL) more closely resemble the pre-implantation embryo inner cell mass than cultures in serum/LIF (SL). Unveiling the differences between both systems is important for understanding development and could also assist in isolating an ESC equivalent for other mammalian species. In SL, pluripotency and cell cycle gene transcription is a multistep process requiring release of promoter-proximal paused RNA polymerase II (Pol2) by the histone acetylation reader BRD4 and the Pol2 kinase CDK9. Here, we show that recruitment of co-regulators including Mediator and Cohesin by β-catenin changes the mode of transcriptional regulation at BRD4/CDK9-bound loci in 2iL. This switch renders pluripotency genes more reliant on transcriptional initiation and less on Pol2 pause release for effective gene body elongation. Conversely, cell cycle genes are not bound by β-catenin and are still dependent on Pol2 pause release. Thus, pluripotency is more resistant to BRD4/CDK9 suppression in 2iL while self-renewal remains highly sensitive. Our findings help to explain how pluripotency is shielded in the ground state and provide insight into transcriptional adaptation upon network perturbation in other contexts.

2020-07-01 | GSE123691 | GEO

β-catenin safeguards the ground state of pluripotency by strengthening the robustness of the transcriptional apparatus [ATAC-seq]

2020-07-01 | GSE123690 | GEO

Generation of Naïve Induced Pluripotent Stem Cells from Rhesus Monkey Fibroblasts

Project description:Conventional embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) derived from primates resemble mouse epiblast stem cells, raising an intriguing question regarding whether the naïve pluripotent state resembling mouse embryonic stem cells (mESCs) exists in primates and how to capture it in vitro. Here we identified several specific signaling modulators that are sufficient to generate rhesus monkey fibroblast-derived iPSCs with the features of naïve pluripotency in terms of growth properties, gene expression profiles, self-renewal signaling, X-reactivation and the potential to generate cross-species chimeric embryos. Interestingly, together with recent reports of naïve human pluripotent stem cells, our findings suggest several conserved signaling pathways shared with rodents and specific to primates, providing significant insights for acquiring naïve pluripotency from other mammal species. In addition, the derivation of rhesus monkey naïve iPSCs also provides a valuable cell source for use in preclinical research and disease modeling. mRNA expression analysis of 4 rhesus monkey naive iPSC lines and 2 primed iPSC lines were examed.

2014-10-14 | E-GEOD-61420 | biostudies-arrayexpress

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