title: Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription.
abstract: 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 intraaortic 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.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences.
authors.forename: Fong Ming
authors.initials: FM
authors.lastname: Koh
authors.affiliation: Cardiovascular Research Institute, and Division of Neonatology, Department of Pediatrics, University of California, San Francisco, CA 94143.
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Lizama
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Wong
authors.affiliation: Cardiovascular Research Institute, and Division of Neonatology, Department of Pediatrics, University of California, San Francisco, CA 94143.
authors.forename: John S
authors.initials: JS
authors.lastname: Hawkins
authors.affiliation: Cardiovascular Research Institute, and Division of Neonatology, Department of Pediatrics, University of California, San Francisco, CA 94143.
authors.forename: Ann C
authors.identifier: http://orcid.org/0000-0003-3298-7308
authors.initials: AC
authors.lastname: Zovein
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences, mrsantos@ucsf.edu.
authors.forename: Miguel
authors.initials: M
authors.lastname: Ramalho-Santos
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014158:Transcription, Genetic
chemical_list: C489844:Chd1 protein, mouse; D002843:Chromatin; D004268:DNA-Binding Proteins
keywords: Chd1; definitive hematopoiesis; endothelial-to-hematopoietic transition; hemogenic endothelium; transcription
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