Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 14, Pages E1734-E1743Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1424850112
Keywords
hemogenic endothelium; endothelial-to-hematopoietic transition; definitive hematopoiesis; transcription; Chd1
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Funding
- National Science Scholarship from the Agency for Science, Technology and Research (A*STAR, Singapore)
- Burroughs Wellcome Fund Career Award for Medical Sciences [1008408.01]
- NIH New Innovator Award [DP2OD009883, DP2OD004698]
- NIH [GM113014]
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Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E) 15.5. Mutant embryos contain normal numbers of E10.5 intra-aortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic-specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts.
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