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The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [ChIP-Seq]

ABSTRACT: We profiled chromatin accessibility in sorted hematopoietic populations. We used this to identify signatures of chromatin accessibility which discriminated LT-HSC from other hematopoietic stem and progenitor cell populations, discriminated by CTCF binding sites. We further validated this with RNA-Seq on sorted cord blood populations following shCTCF, and Hi-C and CTCF ChIP-Seq on the OCIAML-2 cell line.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125061 | GEO | 2020/11/23

REPOSITORIES: GEO

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The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [RNA-Seq]

Project description:We profiled chromatin accessibility in sorted hematopoietic populations. We used this to identify signatures of chromatin accessibility which discriminated LT-HSC from other hematopoietic stem and progenitor cell populations, discriminated by CTCF binding sites. We further validated this with RNA-Seq on sorted cord blood populations following shCTCF, and Hi-C and CTCF ChIP-Seq on the OCIAML-2 cell line.

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The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Hi-C]

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The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [ATAC-Seq]

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The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Low-C]

Project description:Life-long blood production requires long-term hematopoietic stem cells (LT-HSC) - marked by stemness states involving quiescence and self-renewal - to transition into activated short-term HSC (ST-HSC) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk ATAC-seq on human HSC and stem/progenitor subsets (HSPC) to uncover chromatin accessibility signatures, one including LT-HSC (LT/HSPC signature) and another excluding LT-HSC (Act/HSPC signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CTCF binding sites mediating 351 chromatin interactions, engaged in ST-HSC but not LT-HSC, enclosing multiple stemness pathway genes active in LT-HSC and repressed in ST-HSC. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSC from transitioning to activated ST-HSC. Hence, 3D chromatin interactions centrally mediated by CTCF, endow a gatekeeper function that governs the earliest fate transitions HSC make by coordinating disparate stemness pathways linked to quiescence and self-renewal.

2020-11-23 | GSE159287 | GEO

ea9af326-25e0-42af-a639-732a3bafd94b - samples

Project description:To elucidate the epigenetic changes which occur when human long-term hematopoietic stem cells (LT-HSC) become activated we performed Bulk ATAC-Seq on 13 sorted bulk hematopoietic populations from cord bloodas well as single-cell ATAC-Seq upon CD34+CD38-CD45RA- cells enriched for HSC as well as CD34+/CD38+ progenitor cells both from cord blood. These studies revealed gains of chromatin accessibility around CTCF binding sites during HSPC activation, as such we additionally performed Low-C to directly profile the 3D conformation of human cord-blood derived LT-HSC and Short-term hematopoietic stem cells (ST-HSC), as well as Hi-C , ATAC-Seq and CTCF ChIP-Seq upon the OCIAML-2 cell line in which CTCF sites gained during LT-HSC activation are enriched. Finally we transduced human cord-blood LT-HSC with an shCTCF vector; in-vitro cultured LT-HSC cells harbouring shCTCF were used to perform RNA-Seq, and scATAC-Seq was performed on CD34+/CD38- human CB cells transduced with shCTCF, four weeks post xeno-transplantation into mice. Collectively these studies have helped us demonstrate the role of 3D chromatin conformation changes during human LT-HSC activation.

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Project description:Profiling the mRNA content in 293T human embryonic kidney (HEK) cells in the presence and absence of HSF1 or CTCF. The mRNA was enriched from total cellular RNA using using polyadenyltion-selection. HSF1 (shHSF1) or CTCF (shCTCF) was downregulated using shRNA for 48hours. Scrambled RNA (shScr) was used as a negative control.

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Systematic assessment of ISWI subunits reveals that NURF creates local accessibility for proper CTCF function

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2024-03-13 | PXD042945 | Pride

Spatial reorganization of telomeres in long-lived quiescent cells.

Project description:The spatiotemporal behavior of chromatin is an important control mechanism of genomic function. Studies in Saccharomyces cerevisiae have broadly contributed to demonstrate the functional importance of nuclear organization. Although in the wild yeast survival depends on their ability to withstand adverse conditions, most of these studies were conducted on cells undergoing exponential growth. In these conditions, as in most eukaryotic cells, silent chromatin that is mainly found at the 32 telomeres accumulates at the nuclear envelope, forming three to five foci.Here, combining live microscopy, DNA FISH and chromosome conformation capture (HiC) techniques, we report that chromosomes adopt distinct organizations according to the metabolic status of the cell. In particular, following carbon source exhaustion the genome of long-lived quiescent cells undergoes a major spatial re-organization driven by the grouping of telomeres into a unique focus or hypercluster localized in the center of the nucleus. This change in genome conformation is specific to quiescent cells able to sustain long-term viability. We further show that reactive oxygen species produced by mitochondrial activity during respiration commit the cell to form a hypercluster upon starvation. Importantly, deleting the gene encoding telomere associated silencing factor SIR3 abolishes telomere grouping and decreases longevity, a defect that is rescued by expressing a silencing defective SIR3 allele competent for hypercluster formation.Our data show that mitochondrial activity primes cells to group their telomeres into a hypercluster upon starvation, reshaping the genome architecture into a conformation that may contribute to maintain longevity of quiescent cells.

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Acute depletion of CTCF rewires genome-wide chromatin accessibility

Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation

2021-07-04 | PXD026484 | Pride

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