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GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE93147 | GEO | 2018/07/12

REPOSITORIES: GEO

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GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency.

Project description:The enhancer landscape of pluripotent stem cells undergoes extensive reorganization during early mammalian development. The functions and mechanisms behind such reorganization, however, are unclear. Here, we show that the transcription factor GRHL2 is necessary and sufficient to activate an epithelial subset of enhancers as naive embryonic stem cells (ESCs) transition into formative epiblast-like cells (EpiLCs). Surprisingly, many GRHL2 target genes do not change in expression during the ESC-EpiLC transition. Instead, enhancers regulating these genes in ESCs diminish in activity in EpiLCs while GRHL2-dependent alternative enhancers become activated to maintain transcription. GRHL2 therefore assumes control over a subset of the naive network via enhancer switching to maintain expression of epithelial genes upon exit from naive pluripotency. These data evoke a model where the naive pluripotency network becomes partitioned into smaller, independent networks regulated by EpiLC-specific transcription factors, thereby priming cells for lineage specification.

| S-EPMC6456389 | biostudies-literature

GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [ESC & EpiLC]

Project description:During early development, pluripotent cells of the epiblast show extensive rewiring of enhancers with little associated change in gene expression. The mechanisms underlying and purpose of this rewiring are largely unknown. Here we identified a transcription factor, GRHL2, that is both necessary and sufficient to activate latent enhancers during the transition from naïve embryonic stem cells (ESC) to primed epiblast cells (EpiC). GRHL2 is necessary to maintain expression of its targets in EpiCs. However, these genes are already expressed at equivalent levels in ESCs, suggesting these genes switch enhancer usage during the transition. Identification of alternative enhancers driving these genes in ESCs uncovered an enrichment for the ESC-specific KLF transcription factors. While many KLF targets remain expressed in EpiCs, GRHL2 only regulates a specific subset promoting an epithelial program. These data suggest a model where a large naïve-specific transcriptional network is partitioned into smaller networks to uncouple their regulation in EpiCs, providing more flexibility in gene regulation during lineage specification.

2018-07-12 | GSE112749 | GEO

GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [ChIP-Seq]

2018-07-12 | GSE92745 | GEO

GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [WT & KO]

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GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [Illumina MouseRef-8 v2.0 expression]

2018-07-12 | GSE93146 | GEO

GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency

Project description:GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency

| PRJNA360131 | ENA

GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [WT & KO]

Project description:GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [WT & KO]

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GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [ESC & EpiLC]

Project description:GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naïve pluripotency [ESC & EpiLC]

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Brd4-Brd2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification.

Project description:Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance. Mechanistically, BET proteins specifically engage Nodal gene regulatory elements (NREs) to promote Nodal signalling and Smad2 developmental responses. In pluripotent cells, Brd2-Brd4 occupy NREs, but only Brd4 is required for pluripotency gene expression. Brd4 downregulation facilitates pluripotent exit and drives enhanced Brd2 NRE occupancy, thereby unveiling a specific function for Brd2 in differentiative Nodal-Smad2 signalling. Therefore, distinct BET functionalities and Brd4-Brd2 isoform switching at NREs coordinate pluripotent exit with lineage specification.

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Multilayer and MATR3-dependent regulation of mRNAs maintains pluripotency in human induced pluripotent stem cells.

Project description:Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays pleiotropic roles in gene expression regulation by directly stabilizing target RNAs and supporting the activity of transcription factors by modulating chromatin architecture. MATR3 is involved in the differentiation of neural cells, and, here, we elucidate its critical functions in regulating pluripotent circuits in human induced pluripotent stem cells (hiPSCs). MATR3 downregulation affects hiPSCs' differentiation potential by altering key pluripotency regulators' expression levels, including OCT4, NANOG, and LIN28A by pleiotropic mechanisms. MATR3 binds to the OCT4 and YTHDF1 promoters favoring their expression. YTHDF1, in turn, binds the m6A-modified OCT4 mRNA. Furthermore, MATR3 is recruited on ribosomes and controls pluripotency regulating the translation of specific transcripts, including NANOG and LIN28A, by direct binding and favoring their stabilization. These results show that MATR3 orchestrates the pluripotency circuitry by regulating the transcription, translational efficiency, and epitranscriptome of specific transcripts.

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