title: Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity.
abstract: Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.
authors.affiliation: Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Johnson
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Myung-Jeom
authors.initials: MJ
authors.lastname: Ryu
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Boyer
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Lee
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.forename: Sunduz
authors.initials: S
authors.lastname: Keles
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000196:embryology* / Q000473:pathology; D024721:E-Box Elements; D047108:Embryonic Development / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D005804:Genes, Lethal; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006470:Hemorrhage / Q000196:embryology / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008969:Molecular Sequence Data; D009164:Mycobacterium Infections / Q000209:etiology; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D017384:Sequence Deletion
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse