Efficient hemogenic endothelial cell specification by RUNX1 is dependent on baseline chromatin accessibility of RUNX1-regulated TGFβ target genes

Elizabeth D. Howell, Amanda D. Yzaguirre, Peng Gao, Raphael Lis, Bing He, Melike Lakadamyali, Shahin Rafii, Kai Tan, Nancy A. Speck

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are generated de novo in the embryo from hemogenic endothelial cells (HECs) via an endothelial-to-hematopoietic transition (EHT) that requires the transcription factor RUNX1. Ectopic expression of RUNX1 alone can efficiently promote EHT and HSPC formation from embryonic endothelial cells (ECs), but less efficiently from fetal or adult ECs. Efficiency correlated with baseline accessibility of TGFβ-related genes associated with endothelial-to-mesenchymal transition (EndoMT) and participation of AP-1 and SMAD2/3 to initiate further chromatin remodeling along with RUNX1 at these sites. Activation of TGFβ signaling improved the efficiency with which RUNX1 specified fetal ECs as HECs. Thus, the ability of RUNX1 to promote EHT depends on its ability to recruit the TGFβ signaling effectors AP-1 and SMAD2/3, which in turn is determined by the changing chromatin landscape in embryonic versus fetal ECs. This work provides insight into regulation of EndoMT and EHT that will guide reprogramming efforts for clinical applications.

Original languageEnglish (US)
Pages (from-to)1475-1489
Number of pages15
JournalGenes and Development
Volume35
Issue number21-22
DOIs
StatePublished - Nov 1 2021

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

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