Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Genes Dev. 2020 Jul 1;34(13-14):950-964. doi: 10.1101/gad.338202.120. Epub 2020 Jun 4.


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.

Keywords: HSC; embryonic hematopoiesis; enhancer; epigenetics; hemogenic endothelium; regulatory network.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Animals
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic / genetics
  • Epigenesis, Genetic / genetics
  • Gene Editing
  • Gene Expression Regulation, Developmental / genetics*
  • Gene Regulatory Networks / genetics*
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / cytology*
  • Mice
  • Sp3 Transcription Factor / metabolism
  • Transcription Factors / metabolism
  • Transcriptome


  • DNA-Binding Proteins
  • Sp3 protein, mouse
  • Transcription Factors
  • c-MYC-associated zinc finger protein
  • Sp3 Transcription Factor