Widespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA550039 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12694793_1.fastq.gz | Fastqsanger.gz | |||
| SRR12694793_2.fastq.gz | Fastqsanger.gz | |||
| SRR12694794_1.fastq.gz | Fastqsanger.gz | |||
| SRR12694794_2.fastq.gz | Fastqsanger.gz | |||
| SRR12694795_1.fastq.gz | Fastqsanger.gz |
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Project description:The transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generated a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and developed a network-graph approach to examine the atlas at multiple spatial scales. We uncovered highly connected promoter hubs that changed substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merged to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identified widespread state-specific differences in enhancer activity and interactivity that corresponded with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide new, multilayered insights into the chromatin-based gene regulatory control of human pluripotent states.
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Project description:The transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and develop a network-graph approach to examine the atlas at multiple spatial scales. We uncover highly connected promoter hubs that change substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merge to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identify widespread state-specific differences in enhancer activity and interactivity that correspond with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide multilayered insights into the chromatin-based gene regulatory control of human pluripotent states.
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Project description:Pluripotency is the ability of an embryonic stem (ES) cell to differentiate into all the different cell lineages of a mature organism. Naïve and primed pluripotent ES cells in vitro correspond to the pre- and post-implantation populations in the embryo, and they are developmentally linked to each other via progression through a ‘formative’ transition state where naïve ES cells mature in response to inductive cues prior to becoming specified towards certain cell fates. Studying the formative state is thus crucial for understanding the mechanisms of multi-lineage decision-making. Here we show that in the formative state there is a profound reorganisation of 3D genome structure, where genes whose expression levels are changing become located in multi-way chromatin hubs and highly intermingled regions of the genome. Our results suggest that the reorganisation of 3D genome structure is driven by changes in DNA methylation and Polycomb-mediated heterochromatin formation, which is accompanied by a global increase in transcriptional bursting, leading to a reconfiguration of enhancer-promoter interactions – consistent with changes in the epigenome priming promoters for lineage specific gene expression.
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Project description:Serum-to-2i interconversion of mouse Embryonic Stem Cells (mESCs) is a valuable in vitro model for early embryonic development. To assess whether 3D chromatin organization changes during this transition, we established Capture Hi-C with target-sequence enrichment of DNase I hypersensitive sites. We detected extremely long-range intra- and inter-chromosomal interactions between a small subset of H3K27me3 marked bivalent promoters involving the Hox clusters in serum grown cells. Notably, these promoter-mediated interactions are not present in 2i ground-state pluripotent mESCs but appear upon further development into primed-like serum mESCs. Reverting serum mESCs to ground-state 2i mESCs removes these promoter-promoter interactions in a spatiotemporal manner. H3K27me3, which is largely absent at bivalent promoters in ground-state 2i mESCs, is necessary but not sufficient to establish these interactions, as confirmed by Capture Hi-C on Eed-/- serum mESCs. Our results implicate H3K27me3 and PRC2 as critical players in chromatin alteration during priming of ESCs for differentiation. To study dynamics in chromatin architecture and to characterize long-range interaction, we performed Hi-C using DpnII as the restriction enzyme, potentially reaching a genome-wide coverage at a less than 1Kb resolution. We subsequently performed enrichment of interaction by a target capture similar to the exome sequencing approach. We enriched for DNaseI hyper-sensitive sites (DHSâs) in chromatin from mESCs. Probes were designed against the union of all DHSâs of Serum and 2i mESCs. Capture Hi-C reveals Extremely Long-Range Interactions (ELRI) in Serum but not in 2i ESCs. We observed H3K27me3 as a prominent characteristic, but not exclusive feature of ELRI loci in Serum mESCs. To further elucidate the involvement of constituents of PRC1 and PRC2 in ELRI, we performed ChIP-seq experiment on Suz12 and Ring1B during serum-to-2i transition. In addition, RNA-seq was performed to compare the expression levels of genes.
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Project description:Serum-to-2i interconversion of mouse Embryonic Stem Cells (mESCs) is a valuable in vitro model for early embryonic development. To assess whether 3D chromatin organization changes during this transition, we established Capture Hi-C with target-sequence enrichment of DNase I hypersensitive sites. We detected extremely long-range intra- and inter-chromosomal interactions between a small subset of H3K27me3 marked bivalent promoters involving the Hox clusters in serum grown cells. Notably, these promoter-mediated interactions are not present in 2i ground-state pluripotent mESCs but appear upon further development into primed-like serum mESCs. Reverting serum mESCs to ground-state 2i mESCs removes these promoter-promoter interactions in a spatiotemporal manner. H3K27me3, which is largely absent at bivalent promoters in ground-state 2i mESCs, is necessary but not sufficient to establish these interactions, as confirmed by Capture Hi-C on Eed-/- serum mESCs. Our results implicate H3K27me3 and PRC2 as critical players in chromatin alteration during priming of ESCs for differentiation.
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Project description:Interactions between promoters and cis-regulatory elements, such as enhancers, play a role in gene regulation. However, the role of three-dimensional (3D) chromatin structure in orchestrating changes in transcription during cell fate transition is not fully understood. Here, we performed integrated analyses of chromosomal architecture, epigenetics and gene expression using Hi-C, promoter Capture Hi-C (PCHi-C), ChIP sequencing, and RNA sequencing during trans-differentiation of preB cells into macrophages with a β-estradiol inducible CEBPα-ER transgene. Within 1 hour of β-estradiol induction, CEBPα translocates from the cytoplasm to the nucleus and binds to thousands of promoters and putative regulatory elements, resulting in downregulation of preB cell specific genes and induction of macrophage specific genes. Hi-C results were remarkably consistent throughout transinduction, revealing only a small number of TAD boundary location changes, and A/B compartment switches despite changes in expression of thousands of genes. PCHi-C reveals changes in promoter-anchored loops with decrease in interactions parallel with their decreased expression, and new promoter-anchored interactions with macrophage specific genes concordant with their increased expression.Overall, our data demonstrate that CEBPα-induced transinduction involves few changes in genome architecture that are detectable by Hi-C, and widespread reorganization of thousands of promoter anchored loops with PCHi-C that drive changes in cell identity.
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