title: Gata2 cis-element is required for hematopoietic stem cell generation in the mammalian embryo.
abstract: The generation of hematopoietic stem cells (HSCs) from hemogenic endothelium within the aorta, gonad, mesonephros (AGM) region of the mammalian embryo is crucial for development of the adult hematopoietic system. We described a deletion of a Gata2 cis-element (+9.5) that depletes fetal liver HSCs, is lethal at E13-14 of embryogenesis, and is mutated in an immunodeficiency that progresses to myelodysplasia/leukemia. Here, we demonstrate that the +9.5 element enhances Gata2 expression and is required to generate long-term repopulating HSCs in the AGM. Deletion of the +9.5 element abrogated the capacity of hemogenic endothelium to generate HSC-containing clusters in the aorta. Genomic analyses indicated that the +9.5 element regulated a rich ensemble of genes that control hemogenic endothelium and HSCs, as well as genes not implicated in hematopoiesis. These results reveal a mechanism that controls stem cell emergence from hemogenic endothelium to establish the adult hematopoietic system.
authors.affiliation: Department of Cell and Regenerative Biology, Carbone Cancer Center, and 2 McArdle Laboratory for Cancer Research, 3 UW-Madison Blood Research Program; and 4 Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Johnson
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Boyer
authors.forename: Colin N
authors.initials: CN
authors.lastname: Dewey
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D000818:Animals; D001011:Aorta / Q000196:embryology; D002469:Cell Separation; D004742:Enhancer Elements, Genetic; D005260:Female; D005434:Flow Cytometry; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D023281:Genomics; D006066:Gonads / Q000196:embryology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008297:Male; D008650:Mesonephros / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D013234:Stem Cells / Q000166:cytology
chemical_list: D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse