Matthew T Menendez1, E-Ching Ong1, Brian T Shepherd1, Vijay Muthukumar1, Robert Silasi-Mansat1, Florea Lupu1, Courtney T Griffin2. 1. From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (M.T.M., E.-C.O., B.T.S, V.M., R.S.-M., F.L., C.T.G.); and Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City (F.L., C.T.G.). 2. From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City (M.T.M., E.-C.O., B.T.S, V.M., R.S.-M., F.L., C.T.G.); and Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City (F.L., C.T.G.). Courtney-Griffin@omrf.org.
Abstract
OBJECTIVE: The chromatin remodeling enzyme BRG1 (brahma-related gene 1) transcriptionally regulates target genes important for early blood vessel development and primitive hematopoiesis. However, because Brg1 deletion in vascular progenitor cells results in lethal anemia by embryonic day 10.5 (E10.5), roles for BRG1 in embryonic vascular development after midgestation are unknown. In this study, we sought to determine whether endothelial cell BRG1 regulates genes important for vascular development or maintenance later in embryonic development. APPROACH AND RESULTS: Using mice with temporally inducible deletion of endothelial BRG1 (Brg1fl/fl;Cdh5(PAC)-CreERT2 ), we found that Brg1 excision between E9.5 and 11.5 results in capillary dilation and lethal hemorrhage by E14.5. This phenotype strongly resembles that seen when the SRF (serum response factor) transcription factor is deleted from embryonic endothelial cells. Although expression of Srf and several of its known endothelial cell target genes are downregulated in BRG1-depleted endothelial cells, we did not detect binding of BRG1 at these gene promoters, indicating that they are not direct BRG1 target genes. Instead, we found that BRG1 binds to the promoters of the SRF cofactors Mrtfa and Mrtfb (myocardin-related transcription factors A and B) in endothelial cells, and these genes are downregulated in Brg1-deficient endothelial cells. CONCLUSIONS: BRG1 promotes transcription of endothelial Mrtfa and Mrtfb, which elevates expression of SRF and SRF target genes that establish embryonic capillary integrity. These data highlight a new and temporally specific role for BRG1 in embryonic vasculature and provide novel information about epigenetic regulation of Mrtf expression and SRF signaling in developing blood vessels.
OBJECTIVE: The chromatin remodeling enzyme BRG1 (brahma-related gene 1) transcriptionally regulates target genes important for early blood vessel development and primitive hematopoiesis. However, because Brg1 deletion in vascular progenitor cells results in lethal anemia by embryonic day 10.5 (E10.5), roles for BRG1 in embryonic vascular development after midgestation are unknown. In this study, we sought to determine whether endothelial cell BRG1 regulates genes important for vascular development or maintenance later in embryonic development. APPROACH AND RESULTS: Using mice with temporally inducible deletion of endothelial BRG1 (Brg1fl/fl;Cdh5(PAC)-CreERT2 ), we found that Brg1 excision between E9.5 and 11.5 results in capillary dilation and lethal hemorrhage by E14.5. This phenotype strongly resembles that seen when the SRF (serum response factor) transcription factor is deleted from embryonic endothelial cells. Although expression of Srf and several of its known endothelial cell target genes are downregulated in BRG1-depleted endothelial cells, we did not detect binding of BRG1 at these gene promoters, indicating that they are not direct BRG1 target genes. Instead, we found that BRG1 binds to the promoters of the SRF cofactors Mrtfa and Mrtfb (myocardin-related transcription factors A and B) in endothelial cells, and these genes are downregulated in Brg1-deficient endothelial cells. CONCLUSIONS:BRG1 promotes transcription of endothelial Mrtfa and Mrtfb, which elevates expression of SRF and SRF target genes that establish embryonic capillary integrity. These data highlight a new and temporally specific role for BRG1 in embryonic vasculature and provide novel information about epigenetic regulation of Mrtf expression and SRF signaling in developing blood vessels.
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