Combinatorial Regulation of Endothelial Gene Expression by Ets and Forkhead Transcription Factors Sarah De Val,1 Neil C. Chi,1,2 Stryder M. Meadows,3 Simon Minovitsky,4 Joshua P. Anderson,1 Ian S. Harris,1 Melissa L. Ehlers,1 Pooja Agarwal,1 Axel Visel,4 Shan-Mei Xu,1 Len A. Pennacchio,4 Inna Dubchak,4 Paul A. Krieg,3 Didier Y.R. Stainier,1,2 and Brian L. Black1,2,* 1Cardiovascular Research Institute 2Department of Biochemistry and Biophysics University of California, San Francisco, San Francisco, CA 94158-2517, USA 3Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA 4Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA *Correspondence:
[email protected] DOI 10.1016/j.cell.2008.10.049 SUMMARY mechanisms governing gene expression in these processes remain incompletely understood. Vascular development begins when mesodermal The Ets family of winged helix proteins plays a clear role in the cells differentiate into endothelial cells, which then transcriptional control of genes involved in vascular develop- form primitive vessels. It has been hypothesized ment (Dejana et al., 2007; Sato, 2001). All Ets factors share that endothelial-specific gene expression may be a highly conserved DNA-binding domain and bind to the core regulated combinatorially, but the transcriptional DNA sequence GGA(A/T), and nearly every endothelial cell en- mechanisms governing specificity in vascular gene hancer or promoter characterized to date contains multiple es- sential Ets-binding sites (Dejana et al., 2007; Sato, 2001). Of expression remain incompletely understood. Here, the nearly 30 different members of the mammalian Ets family, we identify a 44 bp transcriptional enhancer that is at least 19 are expressed in endothelial cells, and several have sufficient to direct expression specifically and exclu- been shown to play essential roles in vascular development (Hol- sively to the developing vascular endothelium.