ChIP-Seq of Sox2 and Brn2 in ESCs, NPCs, and differentiating ESCs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35496 | GEO | 2013/02/20
SECONDARY ACCESSION(S): PRJNA152295
REPOSITORIES: GEO
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Project description:We analyzed the genome-wide binding of Sox2 and POU factor partner factors, Oct4 in ESCs (using published datasets PMID:18692474 and GSM307137, GSM307154, GSM307155) and Brn2 in NPCs. We found that Sox2 and Oct4 co-occupied a large subset of promoters and enhancers in ESCs, but that Sox2 and Brn2 co-occupy predominantly enhancers. Further, we overexpressed Brn2 in differentiating ESCs and showed that ectopic Brn2 recruited Sox2 to NPC-specific targets, resulting in skewed differentiation towards the neural lineage. Examination of transcription factor binding in ESCs, NPCs, and differentiating ESCs by ChIP-Seq.
2013-02-20 | E-GEOD-35496 | biostudies-arrayexpress
Project description:Embryonic stem cell (ESCs) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF, Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs or NSCs. Here we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to the MORE, and is unaffected by Sox2. ChIP-seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, with MORE sub-types apparent, but no Sox/Oct motif enrichment. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency.
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Project description:Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2 expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2 expressing cells under non-adherent conditions to death by anoikis. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2 expressing cells resistant to therapy and cell death by anoikis.
2020-02-25 | GSE145806 | GEO
Project description:Cellular differentiation requires cells to undergo dramatic but strictly controlled changes in chromatin organization, transcriptional regulation, and protein production and interaction. To understand the regulatory connections between these processes, we applied a multi-omics approach integrating proteomic, transcriptomic, chromatin accessibility, protein occupancy, and protein-chromatin interaction data acquired during differentiation of mouse embryonic stem cells (ESCs) into post-mitotic neurons. We found extensive remodeling of the chromatin that was preceding changes on RNA and protein levels. We found the pluripotency factor Sox2 as regulator of neuron-specific genes and, as a potential mechanism, revealed its genomic redistribution from pluripotency enhancers to neuronal promoters and concomitant change of its protein interaction network upon differentiation. We identified Atrx as a major Sox2 partner in neurons, whose co-localisation correlated with an increase in active enhancer marks and increased expression of nearby genes, and where deletion of a Sox2-Atrx co-bound site resulted in reduced expression of the proximal gene. Collectively, these findings provide key insights into the regulatory transformation of Sox2 during neuronal differentiation and highlight the significance of multi-omic approaches in understanding gene regulation in complex systems.
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Project description:Lineage-specific transcriptional regulators control differentiation states not only during normal development but also during cancer evolution. By investigating super-enhancer landscape of lung squamous cell carcinoma (LUSC), we identified a unique ‘neural’ subtype defined by Sox2 and a neural lineage factor Brn2. Robust protein-protein interaction and genomic co-occupancy of these factors indicated their transcriptional cooperation in this ‘neural’ LUSC in contrast to the cooperation of Sox2 and p63 in the classical LUSC. Introduction of p63 expression in the “neural’ LUSC invoked the classical LUSC lineage accompanied by Brn2 downregulation and increased activities of ErbB/Akt and MAPK-ERK pathways. Collectively, our data demonstrate a unique LUSC lineage featured by Sox2 cooperation with Brn2 instead of p63, for which distinct therapeutic approaches may be warranted.
2019-09-17 | GSE137459 | GEO
Project description:Lineage-specific transcriptional regulators control differentiation states not only during normal development but also during cancer evolution. By investigating super-enhancer landscape of lung squamous cell carcinoma (LUSC), we identified a unique ‘neural’ subtype defined by Sox2 and a neural lineage factor Brn2. Robust protein-protein interaction and genomic co-occupancy of these factors indicated their transcriptional cooperation in this ‘neural’ LUSC in contrast to the cooperation of Sox2 and p63 in the classical LUSC. Introduction of p63 expression in the “neural’ LUSC invoked the classical LUSC lineage accompanied by Brn2 downregulation and increased activities of ErbB/Akt and MAPK-ERK pathways. Collectively, our data demonstrate a unique LUSC lineage featured by Sox2 cooperation with Brn2 instead of p63, for which distinct therapeutic approaches may be warranted.
2019-09-17 | GSE137460 | GEO
Project description:Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis.
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Project description:We showed a novel mechanism in which Ash2l directly binds to super-enhancers of several stemness genes to regulate pluripotency and self-renewal in pluripotent stem cells. Ash2l recruits Oct4/Sox2/Nanog (OSN) to form Ash2l/OSN complex at the super-enhancers of Jarid2, Nanog, Sox2, and Oct4, and further drives enhancer activation, upregulation of stemness genes, and maintains the pluripotent circuitry. Ash2l knockdown abrogates the OSN recruitment to all super-enhancers and further hinders the enhancer activation.
2020-01-24 | GSE136870 | GEO
Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form M-bM-^@M-^\super-enhancersM-bM-^@M-^] at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. Time-course of gene expression following shRNA knockdown of Oct4 and Med12.
2013-02-13 | E-GEOD-44287 | biostudies-arrayexpress
Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form “super-enhancers” at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. ChIP-Seq and controls associated with Super-Enhancers in murine cell types
2013-02-13 | E-GEOD-44286 | biostudies-arrayexpress