Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Peng Gao, Changya Chen, Elizabeth D. Howell, Yan Li, Joanna Tober, Yasin Uzun, Bing He, Long Gao, Qin Zhu, Arndt F. Siekmann, Nancy A. Speck, Kai Tan

Research output: Contribution to journalArticlepeer-review

Abstract

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 fromthe 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.

Original languageEnglish (US)
JournalGenes and Development
Volume34
Issue number13-14
DOIs
StatePublished - Jul 2020

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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