Abstract
The gene activity underlying cell differentiation is regulated by a diverse set of transcription factors (TFs), histone modifications, chromatin structures and more. Although definitive hematopoietic stem cells (HSCs) are known to emerge via endothelial-to-hematopoietic transition (EHT), how the multi-layered epigenome is sequentially unfolded in a small portion of endothelial cells (ECs) transitioning into the hematopoietic fate remains elusive. With optimized low-input itChIP-seq and Hi-C assays, we performed multi-omics dissection of the HSC ontogeny trajectory across early arterial ECs (eAECs), hemogenic endothelial cells (HECs), pre-HSCs and long-term HSCs (LT-HSCs) in mouse embryos. Interestingly, HSC regulatory regions are already pre-configurated with active histone modifications as early as eAECs, preceding chromatin looping dynamics within topologically associating domains. Chromatin looping structures between enhancers and promoters only become gradually strengthened over time. Notably, RUNX1, a master TF for hematopoiesis, enriched at half of these loops is observed early from eAECs through pre-HSCs but its enrichment further increases in HSCs. RUNX1 and co-TFs together constitute a central, progressively intensified enhancer-promoter interactions. Thus, our study provides a framework to decipher how temporal epigenomic configurations fulfill cell lineage specification during development.
Highlights
The gene activity underlying cell differentiation is regulated by a diverse set of transcription factors (TFs), histone modifications, chromatin structures and more
To examine molecular underpinnings in the continuum of hematopoietic stem cells (HSCs) development, early AECs, hemogenic endothelial cells (HECs), pre-HSCs, and long-term HSCs (LT-HSCs) of mouse embryos were isolated from AGM region at embryonic day 10.0 (E10.0) to fetal liver at E14.5 (Fig. 1a, b and Supplementary Fig. 1a–c), as we recently defined[4,10]
We further looked into the temporal interplay between Cluster 3 (C3) topologically associating domains (TADs) connectivity and chromatin states since they were closely associated with hematopoiesis
Summary
The gene activity underlying cell differentiation is regulated by a diverse set of transcription factors (TFs), histone modifications, chromatin structures and more. Definitive hematopoietic stem cells (HSCs) are known to emerge via endothelial-to-hematopoietic transition (EHT), how the multi-layered epigenome is sequentially unfolded in a small portion of endothelial cells (ECs) transitioning into the hematopoietic fate remains elusive. With optimized low-input itChIP-seq and Hi-C assays, we performed multi-omics dissection of the HSC ontogeny trajectory across early arterial ECs (eAECs), hemogenic endothelial cells (HECs), pre-HSCs and long-term HSCs (LT-HSCs) in mouse embryos. HSC regulatory regions are already pre-configurated with active histone modifications as early as eAECs, preceding chromatin looping dynamics within topologically associating domains. There are three waves of hematopoiesis during mouse embryo development, with definitive long-term hematopoietic stem cells (LT-HSCs) arising last at the aorta–gonad–mesonephros (AGM) region[1,2,3]. A better understanding of gene regulation and cell fate decisions requires comprehensive knowledge of the spatial 3D genome organization and its influence on transcriptional output
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