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Oct4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human [CUT&Tag]

ABSTRACT: Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their physical interactome in human ESCs (hESCs) has not been explored thus far. Here we mapped the protein-protein interactions of OCT4 in naive and primed hESCs, revealing extensive connections to ATP-dependent nucleosome remodeling complexes. In naive hESCs, OCT4 is associated with both BRG1 and BRM, the two core ATPases of the BAF complex. Genome-wide location analyses and genetic deletion studies reveal that these two enzymes exert a functionally redundant role in transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs OCT4 cooperates with BRG1 and the transcription factor SOX2 to create an open chromatin architecture at neural lineage associted genes. This work offers insight into the regulation of human stem cell identity and reveals how a common transcription factor utilizes differential BAF complex composition to control distinct transcriptional programs in naive and primed hESCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167988 | GEO | 2021/07/02

REPOSITORIES: GEO

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Oct4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human [ATAC-seq]

Project description:Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their physical interactome in human ESCs (hESCs) has not been explored thus far. Here we mapped the protein-protein interactions of OCT4 in naive and primed hESCs, revealing extensive connections to ATP-dependent nucleosome remodeling complexes. In naive hESCs, OCT4 is associated with both BRG1 and BRM, the two core ATPases of the BAF complex. Genome-wide location analyses and genetic deletion studies reveal that these two enzymes exert a functionally redundant role in transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs OCT4 cooperates with BRG1 and the transcription factor SOX2 to create an open chromatin architecture at neural lineage associted genes. This work offers insight into the regulation of human stem cell identity and reveals how a common transcription factor utilizes differential BAF complex composition to control distinct transcriptional programs in naive and primed hESCs.

2021-07-02 | GSE167979 | GEO

Oct4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human [RNA-seq}

2021-07-02 | GSE168000 | GEO

OCT4 cooperates with distinct chromatin remodelers in naive and primed pluripotent states in human [RNA-Seq]

Project description:Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). We mapped the protein-protein interactions of OCT4 in naive and primed hESCs, revealing extensive connections to ATP-dependent nucleosome remodeling complexes. In naive hESCs, OCT4 is associated with both BRG1 and BRM, the two mutually exclusive ATPase subunits of the BAF complex. Genome-wide location analyses and genetic deletion studies reveal that these two enzymes exert a functionally redundant role in transcriptional regulation of blastocyst-specific genes. In contrast, OCT4 cooperates with BRG1 and the transcription factor SOX2 to create an open chromatin architecture at neural lineage-associated genes in primed hESCs. This work offers insight into the regulation of human stem cell identity and reveals how a common transcription factor utilizes differential compositions of the BAF complex in controlling distinct transcriptional programs governing naive vs. primed human pluripotent states.

2021-07-01 | GSE147750 | GEO

OCT4 cooperates with distinct chromatin remodelers in naive and primed pluripotent states in human [ChIP-Seq]

Project description:Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). We mapped the protein-protein interactions of OCT4 in naive and primed hESCs, revealing extensive connections to ATP-dependent nucleosome remodeling complexes. In naive hESCs, OCT4 is associated with both BRG1 and BRM, the two mutually exclusive ATPase subunits of the BAF complex. Genome-wide location analyses and genetic deletion studies reveal that these two enzymes exert a functionally redundant role in transcriptional regulation of blastocyst-specific genes. In contrast, OCT4 cooperates with BRG1 and the transcription factor SOX2 to create an open chromatin architecture at neural lineage-associated genes in primed hESCs. This work offers insight into the regulation of human stem cell identity and reveals how a common transcription factor utilizes differential compositions of the BAF complex in controlling distinct transcriptional programs governing naive vs. primed human pluripotent states.

2021-07-01 | GSE147716 | GEO

OCT4 IP-MS in Naive and Primed Human ESCs

2021-09-12 | PXD026556 | Pride

BAF Complex Enhances Reprogramming of Adult Human Fibroblasts

Project description:Chromatin remodeling molecules of the BAF complex, Brg1 and Baf155, as well as other chromatin remodeling modeling molecules have been described to enhance Oct4, Sox2, Klf4 and c-Myc mediated reprogramming of mouse somatic cells into induced pluripotent stem cells (iPSCs). Brg1 maintains pluripotency of mouse embryonic stem cells (mESCs) by modulating the expression of pluripotency genes including Oct4 in synergism with LIF/STAT signaling. Interestingly, unlike mESCs, BAF complex in human embryonic stem cells (hESCs) is composed of both BAF155 and BAF170, where BAF170 plays a role in maintaining hESCs pluripotency. In this study, we describe that BRG1 and BAF155 enhance reprogramming of adult human fibroblasts. Overexpression of BAF155 does not affect pluripotency of hiPSCs as tested by global gene expression profiling as well as in vivo and in vitro assays. Additionally, these findings show that BRG1 and BAF155 expression can enhance reprogramming even in the absence of LIF/STAT signaling.

2018-11-29 | GSE75568 | GEO

Systematic Identification of Defined Conditions for Induction and Maintenance of Naive Human Pluripotency [ChIP-Seq]

Project description:Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support autonomous self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate a homogeneous population of human pluripotent stem cells in which transcription factors associated with the ground state of pluripotency are highly upregulated. Comparison with previously reported naive human ESCs indicates that our kinase inhibitor cocktail captures a novel pluripotent state in humans that closely resembles mouse ESCs. ChIP-seq data from human embryonic stem cells in naive and primed conditions were generated by deep sequencing using Illumina Hi-Seq 2000.

2014-07-16 | E-GEOD-59434 | biostudies-arrayexpress

Novel culture conditions facilitating the induction of naïve pluripotency in human embryonic stem cells

Project description:We report a novel culture condition inducing naive pluripotency in hESCs in a rapid, robust and reproducible way. These naive hESCs were similar to mESCs exhibiting domed colony morphology, increased single survival, reduced doubling time, upregulation of naive pluripotency-specific genes, unbiased lineage-specific differentiation, hypomethylation, separate clustering profile from parental primed hESCs and were dependent on signalling pathways similar to naive mESCs. Global DNA methylation analysis of naive hESCs and their parental primed hESC counterparts.

2015-06-29 | E-GEOD-57318 | biostudies-arrayexpress

Systematic Identification of Defined Conditions for Induction and Maintenance of Naive Human Pluripotency [expression]

Project description:Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support autonomous self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate a homogeneous population of human pluripotent stem cells in which transcription factors associated with the ground state of pluripotency are highly upregulated. Comparison with previously reported naive human ESCs indicates that our kinase inhibitor cocktail captures a novel pluripotent state in humans that closely resembles mouse ESCs. Expression analysis was performed on two groups of human ESC samples: WIBR2 (P12 and P14), WIBR3 (P9) and WIN1 (P10) human ESCs derived in our optimized naive medium (5i/L/A or 6i/L/A, as indicated), and parental WIBR2 and WIBR3 human ESCs in primed human ESC medium.

2014-07-16 | E-GEOD-59430 | biostudies-arrayexpress

Novel culture conditions facilitating the induction of naïve pluripotency in human embryonic stem cells

Project description:It is now well recognized that human embryonic stem cells (hESCs)1 closely resemble mouse epiblast stem cells (mEpiSCs)2-5 exhibiting primed pluripotency unlike mouse ESCs (mESCs) which acquire a naïve pluripotent state4-8. Efforts have been made to trigger naïve pluripotency in hESCs9-11 for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines12. We report here a novel culture medium facilitating rapid induction of naïve pluripotency in established hESCs. Our medium also allows derivation of naïve mESCs from blastocyst stage which has not been shown earlier. The established naïve hESCs could survive long-term single cell passaging, maintain a normal karyotype, exhibit upregulation of naïve pluripotency genes and were dependent on signaling pathways similar to naïve mESCs. Also, they undergo global DNA demethylation, cluster together with previously described naïve hESCs13 and show a distinctive long non-coding RNA profile. Collectively, we demonstrate an alternate route to capture naïve pluripotency in hESCs which is fast, reproducible, can be employed to derive naïve mESCs and can induce efficient differentiation. Three primed and matching naive human embryonic stem cell lines were profiled in duplo.

2015-06-08 | E-GEOD-57271 | biostudies-arrayexpress

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