Genetic framework for GATA factor function in vascular biology

Amelia K. Linnemann, Henriette O'Geen, Sunduz Keles, Peggy J. Farnham, Emery H. Bresnick

Research output: Contribution to journalArticle

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13641-13646
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number33
DOIs
StatePublished - Aug 16 2011
Externally publishedYes

Keywords

  • Endothelium
  • Genome-wide
  • Genomics
  • Transcriptome

ASJC Scopus subject areas

  • General

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