Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells

Chen, Changya; Yu, Wenbao; Tober, Joanna; Gao, Peng; He, Bing; Lee, Ki-Won; Trieu, Tuan; Blobel, Gerd A.; Speck, Nancy A.; Tan, Kai

doi:10.1016/j.celrep.2019.11.065

Cited by 53 publications

(42 citation statements)

References 83 publications

(76 reference statements)

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“…S7A), while 4.4 enhancers contact a promoter (Supplemental Fig. S7B), consistent with results from recent large-scale chromatin interaction studies of EP interactions (Javierre et al 2016;Chen et al 2019). Only ∼14.3% of EP pairs had no intervening promoters from unrelated genes (Supplemental Fig.…”

Section: Diverse Activity Profiles Of Developmental Enhancers During Hsc Ontogenysupporting

confidence: 88%

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

et al. 2020

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Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched population of prehematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are active, suggesting the vast majority of enhancers are established de novo without prior priming in earlier stages. We constructed developmental stage-specific transcriptional regulatory networks by linking enhancers and predicted bound transcription factors to their target promoters using a novel computational algorithm, target inference via physical connection (TIPC). TIPC predicted known transcriptional regulators for the endothelial-to-hematopoietic transition, validating our overall approach, and identified putative novel transcription factors, including the broadly expressed transcription factors SP3 and MAZ. Finally, we validated a role for SP3 and MAZ in the formation of hemogenic endothelium. Our data and computational analyses provide a useful resource for uncovering regulators of HSC formation.

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Section: Diverse Activity Profiles Of Developmental Enhancers During Hsc Ontogenysupporting

confidence: 88%

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

et al. 2020

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“…HPC7 cells express Helios and comprise a mix of cells with LSK and LK features ( Fig. S4 A ), which differentiate into multiple hematopoietic lineages in the presence of appropriate cytokines and retain multipotency in vivo ( Pinto do O et al, 1998 ; Chen et al, 2019 ). Our results revealed 15,709 Helios-bound peaks that mapped near 8,739 genes; binding was observed at gene bodies, distal regions, and proximal promoters ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells

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et al. 2021

Journal of Experimental Medicine

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Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.

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“…cis-REs (CREs) are distributed across the whole genome, and their histone signature correlates with the transcriptional control they exert over their target genes (Hawkins et al 2010;Choukrallah et al 2015;Chen et al 2019). The activation of CREs depends on several epigenetic features, including combinations of different transcription factors' binding sites, and it is positively correlated with the H3K27ac histone modification signal (Heintzman et al 2007;Heinz et al 2015).…”

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confidence: 99%

Enhancers with tissue-specific activity are enriched in intronic regions

et al. 2021

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Tissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We find that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, whereas housekeeping genes are more often controlled by intergenic enhancers, common to many tissues. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, whereas the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.

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Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells

Cited by 53 publications

References 83 publications

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells

Enhancers with tissue-specific activity are enriched in intronic regions

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