Reorganization of enhancer patterns in transition from naïve to primed pluripotency
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Christa Buecker
PROVIDER: E-GEOD-56138 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Naïve and primed pluripotency is characterized by distinct signaling requirements, transcriptomes and developmental properties, but both cellular states share key transcriptional regulators, Oct4, Sox2 and Nanog. Here we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even in the absence of other differentiation cues, premature Otx2 overexpression is sufficient to exit the naïve state, induce transcription of a large subset of primed pluripotency-associated genes and redirect Oct4 to thousands of previously inaccessible sites. However, ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites and signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that capacity of transcription factors such as Otx2 and Oct4 to function as pioneers is highly context-dependent ChIP-seq analysis was performed to map enhancers and associated transcription factors. We used H3K27ac, H3K4me1 and p300 to call enhancers from 2 different pluripotent cell states: ESC and EpiLC. In addition we performed ChIP-seq for Oct4 and Otx2 from these cell states. All these experiments were carried out in replicates, for the EpiLC state the replicates were performed with and without ActivinA. Additionally we carried out ChIPseq for Otx2 and Oct4 in Otx2ko cell lines in which we integrated an inducible Otx2 gene before and after induction with doxycycline.
2014-06-05 | E-GEOD-56098 | biostudies-arrayexpress
Project description:Naïve and primed pluripotency is characterized by distinct signaling requirements, transcriptomes and developmental properties, but both cellular states share key transcriptional regulators, Oct4, Sox2 and Nanog. Here we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even in the absence of other differentiation cues, premature Otx2 overexpression is sufficient to exit the naïve state, induce transcription of a large subset of primed pluripotency-associated genes and redirect Oct4 to thousands of previously inaccessible sites. However, ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites and signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that capacity of transcription factors such as Otx2 and Oct4 to function as pioneers is highly context-dependent transcription profile of ESCs and EpiLCs to analzye changes during differentiation and the effect of Otx2 loss and overexpression on the differentiation properties
2014-06-05 | E-GEOD-56096 | biostudies-arrayexpress
Project description:Prdm14 is a sequence-specific transcriptional regulator of embryonic stem cell (ESC) pluripotency and primordial germ cell (PGC) formation. It exerts its function, at least in part, through repressing genes associated with epigenetic modification and cell differentiation. Here, we show that this repressive function is mediated through an ETO-family co-repressor Mtgr1, which tightly binds to the pre-SET/SET domains of Prdm14 and co-occupies its genomic targets in mouse ESCs. Structure-guided point mutants abrogated the Prdm14-Mtgr1 association and disrupted Prdm14's function in mESC gene expression and PGC formation in vitro. Altogether, our work uncovers the molecular mechanism underlying Prdm14-mediated repression. Examination of Prdm14 and Mtgr1 occupancy by ChIP-seq and effects on gene expression in mouse embryonic stem cells
2016-07-03 | E-GEOD-74547 | biostudies-arrayexpress
Project description:We studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale TAD repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic cell specific genome structures while establishing an embryonic stem cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable discerning their cell-of-origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin dependent gene expression patterns. ChIPseq for CTCF and H3K27ac was performed on early and late iPS cells derived from different founders
2016-03-01 | E-GEOD-76478 | biostudies-arrayexpress
Project description:Background: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells containing a single X chromosome. We use mouse female Embryonic Stem Cells (ESCs) with nonrandom XCI and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome (Xi) by high-resolution allele-specific RNA-Seq. Results: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center (XIC) are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Using allele-specific RNA-Seq of Neural Progenitor Cells (NPCs) generated from the female ESCs, we identify three regions distal to the XIC that stably escape XCI during differentiation of the female ESCs, as well as during propagation of the NPCs. These regions coincide with Topologically Associated Domains (TADs) as determined in the undifferentiated female ESCs. Also the previously characterized human gene clusters escaping XCI correlate with TADs. Conclusions: Together, the dynamics of gene silencing observed over the Xi during XCI provide further insight in the formation and maintenance of the repressive Xi complex. The association of regions of escape with TADs, in mouse and human, suggests a regulatory role for TADs during propagation of XCI. 19 RNA-Seq profiles of mouse ESCs, EpiSCs and NPCs, mostly from distant crosses to allow allele specific mapping. 1 HiC profile of an undifferentiated mouse female ESC line containing a Tsix mutation. Mainly focusing on X inactivation.
2015-06-15 | E-GEOD-60738 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-03-01 | E-GEOD-76481 | biostudies-arrayexpress
Project description:We studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale TAD repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic cell specific genome structures while establishing an embryonic stem cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable discerning their cell-of-origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin dependent gene expression patterns. Transcriptome analysis was performed in somatic cells (NSC, macrophages, MEFs and pre-B cells) and their corresponding early and late induced pluripotent stem cells. In addition, expression analysis was performed in E14 embryonic stem cells
2016-03-01 | E-GEOD-76480 | biostudies-arrayexpress
Project description:We studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale TAD repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic cell specific genome structures while establishing an embryonic stem cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable discerning their cell-of-origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin dependent gene expression patterns. Hi-C was performed in somatic cells (NSC, macrophages, MEFs and pre-B cells) and their corresponding early and late induced pluripotent stem cells. In addition Hi-C was performed in E14 embryonic stem cells
2016-03-01 | E-GEOD-76479 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-06-03 | E-GEOD-57701 | biostudies-arrayexpress
Project description:We assessed the genome-wide binding of the histone acetylase MOF and members of its two associated complexes, the male-specific lethal and the non-specific lethal complex (MSL, NSL). We generated ChIP-seq profiles for MOF, MSL1, MSL2, KANSL3, and MCRS1 from mouse embryonic stem cells and neuronal progenitor cells. By using two replicates per sample and stringent filtering criteria, we identify five basic groups of genome regions where the proteins show either mutual or exclusive binding. We find that the NSL complex members (KANSL3, MCRS1) target the TSSs of broadly expressed genes with housekeeping functions in both cell types. MOF and particularly the MSL complex target a subset of these NSL-complex-targets, too. In addition, we find several thousand TSS-distal binding sites, particularly in ESCs, where KANSL3, MSL2 and MCRS1 show strong enrichments for annotated ESC enhancers. The vast majority of the binding to these ESC distal regulatory elements is lost in NPCs. Finally, we identify mostly intronic and intergenic regions with predominant MSL2 enrichments without the presence of its known interactors. These binding sites do not overlap with ESC marks of active chromatin (e.g. DNase hypersensitivity sites), but the they increase in number upon differentiation and we detect a strong signature of the (CAGA)n motif. Our study provides the first comprehensive analysis of MOF in the context of its two complexes in the mouse and reveals shared as well as distinct and dynamic functions for gene regulation and pluripotency. ChIP-seq of MOF and members of its associated complexes (MSL complex: MSL1, MSL2; NSL complex: KANSL3, MCRS1) in male mouse embryonic stem cells and neuronal progenitor cells derived from them.
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