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Switch Enhancer Elements Control Cell Fate in Human Embryonic Stem Cells (BeadChip)

ABSTRACT: A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the TGFβ pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex comprised of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGFβ pathway (SMAD2/3) and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression, while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52439 | GEO | 2013/12/18

SECONDARY ACCESSION(S): PRJNA228930

REPOSITORIES: GEO

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Switch Enhancer Elements Control Cell Fate in Human Embryonic Stem Cells (BeadChip)

Project description:A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the TGFβ pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex comprised of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGFβ pathway (SMAD2/3) and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression, while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development. Total RNA was isolated from human embryonic stem cells (WA09) 48h after siRNA transfection (siCntr, siTAZ/YAP, siTEAD1-4)

2013-12-18 | E-GEOD-52439 | biostudies-arrayexpress

Switch Enhancer Elements Control Cell Fate in Human Embryonic Stem Cells (ChIP-Seq)

Project description:A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the TGFβ pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex comprised of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGFβ pathway (SMAD2/3) and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression, while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development. ChIP experiment, a total of 8 samples: 4 samples DMSO treated (Input ctr, IgG ctr, SMAD2 precipitation, TEAD4 precipitation), 4 samples SB431542 (Input ctr, IgG ctr, SMAD2 precipitation, TEAD4 precipitation)

2013-12-18 | E-GEOD-52437 | biostudies-arrayexpress

Switch Enhancer Elements Control Cell Fate in Human Embryonic Stem Cells (ChIP-Seq)

2013-12-18 | GSE52437 | GEO

HEB and E2A function as SMAD/FOXH1 cofactors

Project description:Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We have identified a new motif, termed SMAD Complex Associated (SCA) that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two bHLH proteins - HEB and E2A - bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Further, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E2A is a novel Nodal signaling cofactor that associates with SMAD2/3 and FOXH1 and is necessary for mesendoderm differentiation. ChIP-seq of Smad2/3 and Input in X.tropicalis, stage 10.5 embryo.

2011-08-23 | E-GEOD-30146 | biostudies-arrayexpress

HEB and E2A function as SMAD/FOXH1 cofactors

2011-08-23 | GSE30146 | GEO

Single cell RNA sequencing of naive and primed human pluripotent stem cells treated with SB431542

Project description:The aim of this experiment was to investigate the role of TGFβ signalling in human pluripotency, looking at the effect of SB431542 (SB), a potent and selective SMAD inhibitor that blocks TGFβ/Activin receptors ALK5, ALK4, and ALK7, on gene expression. We performed 10X sequencing in naïve and primed human pluripotent stem cells (hPSCs) during a time-course of SB treatment.

2021-08-13 | E-MTAB-10018 | biostudies-arrayexpress

Chromatin and Transcriptional Signatures for Nodal Signaling During Endoderm Formation in hESCs

Project description:To elucidate the Nodal transcriptional network that governs endoderm formation, we used ChIP-Seq to identify genomic targets for SMAD2/3, SMAD3, SMAD4, FOXH1 and the active and repressive chromatin marks, H3K4me3 and H3K27me3, in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that while SMAD2/3, SMAD4 and FOXH1 target binding is highly dynamic, there is an optimal signature for driving endoderm commitment. Initially, this signature is marked by both H3K4me3 and H3K27me3 as a very broad bivalent domain in hESCs. Within the first 24 hours, at a few select promoters, SMAD2/3 accumulation coincides with H3K27me3 depletion so that these loci become selectively monovalent marked only by H3K4me3. The correlation between SMAD2/3 binding, monovalent formation and transcriptional activation suggests a mechanism by which SMAD proteins coordinate with chromatin at critical promoters to drive endoderm specification. Examination of 2 different histone modifications and 4 different transcription factor associations in 2 cell types. For transcription factor analysis, three biological replicate ChIPs were pooled from each antibody, as well as input controls, for both hESCs and derived endoderm. For histone modifications, two biological replicates for H3K4me3 and three for H3K27me3 were used.

2011-05-21 | E-GEOD-29422 | biostudies-arrayexpress

Genome-wide view of TGFb/Foxh1 regulation of the early mesendoderm program [ChIP-seq]

Project description:We defined the genome-wide binding regions of Smad2/3 and Foxh1 at mid-gastrula stage Xenopus tropicalis embryos, at which Nodal signaling and Foxh1 are critical in mesendoderm specification program.

2014-11-07 | GSE53652 | GEO

Chromatin and Transcriptional Signatures for Nodal Signaling During Endoderm Formation in hESCs

2011-05-21 | GSE29422 | GEO

Xenopus tropicalis

Project description:HEB and E2A function as SMAD/FOXH1 cofactors

| PRJNA143851 | ENA