Pre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos

Chen C. Li, Guangyu Zhang, Junjie Du, Di Liu, Zongcheng Li, Yanli Ni, Jie Zhou, Yunqiao Li, Siyuan Hou, Xiaona Zheng, Yu Lan (), Bing Liu () and Aibin He ()
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Chen C. Li: Peking University
Guangyu Zhang: Academy of Military Sciences
Junjie Du: Academy of Military Sciences
Di Liu: Peking University
Zongcheng Li: Fifth Medical Center of Chinese PLA General Hospital
Yanli Ni: Fifth Medical Center of Chinese PLA General Hospital
Jie Zhou: Fifth Medical Center of Chinese PLA General Hospital
Yunqiao Li: Academy of Military Sciences
Siyuan Hou: Jinan University
Xiaona Zheng: Academy of Military Sciences
Yu Lan: Jinan University
Bing Liu: Academy of Military Sciences
Aibin He: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28018-z

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