Epigenetic and Epitranscriptomic Factors Make a Mark on Hematopoietic Stem Cell Development

Kasper, Dionna M.; Nicoli, Stefania

doi:10.1007/s40778-018-0113-0

Cited by 8 publications

(11 citation statements)

References 64 publications

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“…One possibility is that Runx1 expression may be actively repressed in the majority of pre-HE cells by TFs such as Sox17 (Bos et al, 2015;Lizama et al, 2015), which is highly expressed in pre-HE, and binding sites for which are accessible in pre-HE. A requirement for chromatin remodeling may also be a limiting factor in pre-HE, as multiple epigenetic regulatory proteins have been shown to affect Runx1 expression in HE, some of which may act at the pre-HE to HE transition (Kasper and Nicoli, 2018).…”

Section: Discussionmentioning

confidence: 99%

Developmental trajectory of prehematopoietic stem cell formation from endothelium

Zhu

Gao

Tober

et al. 2020

Blood

144

163

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Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow are derived from a small population of hemogenic endothelial (HE) cells located in the major arteries of the mammalian embryo. HE cells undergo an endothelial to hematopoietic cell transition (EHT), giving rise to HSPCs that accumulate in intra-arterial clusters (IAC) before colonizing the fetal liver. To examine the cell and molecular transitions between endothelial (E), HE, and IAC cells, and the heterogeneity of HSPCs within IACs, we profiled ~37,000 cells from the caudal arteries [dorsal aorta (DA), umbilical (U), vitelline (V)] of embryonic day 9.5 (E9.5) to E11.5 mouse embryos by single-cell RNA sequencing (scRNA-Seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-Seq). We identified a continuous developmental trajectory from E to HE to IAC cells, with identifiable intermediate stages. The intermediate stage most proximal to HE, which we term pre-HE, is characterized by increased accessibility of chromatin enriched for SOX, FOX, GATA, and SMAD motifs. A developmental bottleneck separates pre-HE from HE, with RUNX1 dosage regulating the efficiency of the pre-HE to HE transition. A distal candidate Runx1 enhancer exhibits high chromatin accessibility specifically in pre-HE cells at the bottleneck, but loses accessibility thereafter. Distinct developmental trajectories within IAC cells result in two populations of CD45+ HSPCs; an initial wave of lympho-myeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs). This multi-omics single-cell atlas significantly expands our understanding of pre-HSC ontogeny.

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Section: Discussionmentioning

confidence: 99%

Developmental trajectory of prehematopoietic stem cell formation from endothelium

Zhu

Gao

Tober

et al. 2020

Blood

144

163

View full text Add to dashboard Cite

show abstract

“…One possibility is that Runx1 expression may be actively repressed in the majority of pre-HE cells by TFs such as Sox17 Lizama et al, 2015), which is highly expressed in pre-HE, and binding sites for which are accessible in pre-HE. A requirement for chromatin remodeling may also be a limiting factor in pre-HE, as multiple epigenetic regulatory proteins have been shown to affect Runx1 expression in HE, some of which may act at the pre-HE to HE transition (Kasper and Nicoli, 2018).…”

Section: Discussionmentioning

confidence: 99%

Developmental trajectory of pre-hematopoietic stem cell formation from endothelium

Zhu

Gao

Tober

et al. 2019

Preprint

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SummaryHematopoietic stem and progenitor cells (HSPCs) differentiate from hemogenic endothelial (HE) cells through an endothelial to hematopoietic cell transition (EHT). Newly formed HSPCs accumulate in intra-arterial clusters (IACs) before colonizing the fetal liver. To examine the cell and molecular transitions during the EHT, and the heterogeneity of HSPCs within IACs, we profiled ∼37,000 cells from the caudal arteries of embryonic day 9.5 (E9.5) to E11.5 mouse embryos by single-cell transcriptome and chromatin accessibility sequencing. We identified an intermediate developmental stage prior to HE that we termed pre-HE, characterized by increased accessibility of chromatin enriched for SOX, FOX, GATA, and SMAD motifs. A developmental bottleneck separates pre-HE from HE, with RUNX1 dosage regulating the efficiency of the pre-HE to HE transition. Distinct developmental trajectories within IAC cells result in two populations of CD45+ HSPCs; an initial wave of lympho-myeloid-biased progenitors, followed by precursors of hematopoietic stem cells (pre-HSCs).

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“…Through the progressive loss of endothelial gene expression and concomitant increase in hematopoietic potential 1–4,13 , hemECs give birth to nascent HSPCs that delaminate from the vascular wall into the circulation to colonize secondary hematopoietic organs 6–8 . This process is highly regulated, involving a precise interplay between multiple developmentally-timed signaling pathways 1–5,13–16 . It is currently unclear whether such precision is achieved exclusively by the regulation of positive hematopoietic regulators, or whether yet-unknown inhibitory pathways play a role in EHT dynamics.…”

Section: Figurementioning

confidence: 99%

“…During development, hemogenic endothelial cells undergo an endothelial-to-hematopoietic transition (EHT) to generate HSPCs 1–4 . Growth factors and epigenetic changes can promote EHT 1,3,5 , but these mechanisms do not explain its tight spatiotemporal regulation during development. Here, we show that microRNA (miR) miR-223-mediated regulation of N-glycan biosynthesis intrinsically restrains EHT, representing the first pathway that prevents excessive HSPC production.…”

mentioning

confidence: 98%

The N-Glycome regulates the endothelial-to-hematopoietic transition

Kasper

Hintzen

et al. 2019

Preprint

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20Hematopoietic stem and progenitor cells (HSPCs) are required to establish and maintain the 21 adult blood system in vertebrates. During development, hemogenic endothelial cells undergo an 22 endothelial-to-hematopoietic transition (EHT) to generate HSPCs 1-4 . Growth factors and 23 epigenetic changes can promote EHT 1,3,5 , but these mechanisms do not explain its tight 24 spatiotemporal regulation during development. Here, we show that microRNA (miR) miR-223-25 mediated regulation of N-glycan biosynthesis intrinsically restrains EHT, representing the first 26 pathway that prevents excessive HSPC production. We find that miR-223 is uniquely expressed 27 in hemogenic endothelial cells undergoing EHT and in nascent HSPCs. Loss of miR-223 28 promotes the expansion of these cells in the zebrafish and mouse aorta-gonad-mesonephros 29 (AGM), where EHT occurs 6-8 . miR-223 targets alg2 (α1,3/ α1,6 mannosyltransferase) and 30 st3gal2 (α2,3 sialyltransferase) for repression in the AGM endothelium. These two enzymes are 31 involved in the biosynthesis of N-glycans, a common co-translational modification 9,10 that 32 influences several pathophysiological processes 11,12 , but has not yet been implicated in EHT. 33 Using an N-glycosensor, we demonstrate that vascular N-glycosylation increases during EHT, 34 and this process is disrupted upon loss of miR-223. Specifically, high-throughput glycome 35 analysis revealed terminal α1,3 mannose and α2,3 sialic acid modifications of membrane 36 proteins are altered upon loss of miR-223. Importantly, pharmacological manipulation targeting 37 these N-glycan types in wild-type embryos phenocopies the loss of miR-223 and enhances EHT 38 as well as HSPC production. Thus, the N-glycome plays a previously unappreciated role as an 39 intrinsic negative regulator of EHT, with specific mannose and sialic acid modifications serving 40as key endothelial determinants of the hematopoietic fate. 41 43Zebrafish endothelial-to-hematopoietic transition (EHT) has emerged as an instrumental 44 model to understand the formation and regulation of definitive hematopoietic stem and 45 progenitor cells (HSPCs) with long-term engraftment capability. As in their mammalian 46 counterparts, EHT occurs in endothelial cells that co-express vascular and hematopoietic genes 47

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Epigenetic and Epitranscriptomic Factors Make a Mark on Hematopoietic Stem Cell Development

Cited by 8 publications

References 64 publications

Developmental trajectory of prehematopoietic stem cell formation from endothelium

Developmental trajectory of prehematopoietic stem cell formation from endothelium

Developmental trajectory of pre-hematopoietic stem cell formation from endothelium

The N-Glycome regulates the endothelial-to-hematopoietic transition

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