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.

GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome

“…While several of the genes, including RUNX1, NOTCH1, ETS1, and IKBKG, have GATA2 binding sites within the gene region, GATA2 is classified as a remote element preferential transcription factor and commonly occupies chromatin in nonpromoter regions that can be intronic or large distances (.20 kb) away. 15,34,35 Of the original 16 patients with MonoMAC syndrome described by Vinh et al, 1 12 had identified GATA2 mutations. 2 We have demonstrated that the 4 probands not previously associated with exonic GATA2 mutations have GATA2 haploinsufficiency due either to intron 5 mutations or reduced expression of 1 GATA2 allele.…”

GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity

“…39,40 GATA2 was first identified as an endothelial transcription factor, and its haploinsufficiency perturbs normal vascular development. 20,[41][42][43] Thrombotic events in one quarter of patients suggest an association between GATA2 deficiency and coagulopathy, more likely the result of endothelial rather than coagulation abnormalities. In the lymphatic endothelium, GATA2 is involved in the development of lymphatic valves, deficiency of which likely underlies lymphedema.…”

GATA2 is required for lymphatic vessel valve development and maintenance

“…This observation, coupled with our demonstration that GATA2 regulates genes important for lymphatic vessel valve development, prompted us to investigate whether GATA2 mutations result in lymphedema due to defective valve development and/or function. While several earlier studies implicated GATA2 in vascular development (5)(6)(7)(8), the lack of an obvious vascular phenotype in Gata2 -/-mice prior to their demise around E10.5 has precluded in depth analyses of Gata2 function in vasculogenesis and angiogenesis. SNPs in GATA2 have been associated with coronary artery disease (9)(10)(11), implying a role for GATA2 in arterial development, while ablation of gata2a in zebrafish affects morphogenesis of the dorsal aorta (12).…”