title: Genetic framework for GATA factor function in vascular biology.
abstract: Vascular endothelial dysfunction underlies the genesis and progression of numerous diseases. Although the GATA transcription factor GATA-2 is expressed in endothelial cells and is implicated in coronary heart disease, it has been studied predominantly as a master regulator of hematopoiesis. Because many questions regarding GATA-2 function in the vascular biology realm remain unanswered, we used ChIP sequencing and loss-of-function strategies to define the GATA-2-instigated genetic network in human endothelial cells. In contrast to erythroid cells, GATA-2 occupied a unique target gene ensemble consisting of genes encoding key determinants of endothelial cell identity and inflammation. GATA-2-occupied sites characteristically contained motifs that bind activator protein-1 (AP-1), a pivotal regulator of inflammatory genes. GATA-2 frequently occupied the same chromatin sites as c-JUN and c-FOS, heterodimeric components of AP-1. Although all three components were required for maximal AP-1 target gene expression, GATA-2 was not required for AP-1 chromatin occupancy. GATA-2 conferred maximal phosphorylation of chromatin-bound c-JUN at Ser-73, which stimulates AP-1-dependent transactivation, in a chromosomal context-dependent manner. This work establishes a link between a GATA factor and inflammatory genes, mechanistic insights underlying GATA-2-AP-1 cooperativity and a rigorous genetic framework for understanding GATA-2 function in normal and pathophysiological vascular states.
authors.affiliation: Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Linnemann
authors.forename: Henriette
authors.initials: H
authors.lastname: O'Geen
authors.forename: Sunduz
authors.initials: S
authors.lastname: Keles
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D002843:Chromatin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D041905:Erythroid Cells; D050989:GATA2 Transcription Factor / Q000235:genetics*; D053263:Gene Regulatory Networks; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D007249:Inflammation / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics*
chemical_list: D002843:Chromatin; D050989:GATA2 Transcription Factor; D018808:Transcription Factor AP-1