Epigenetic regulators play important roles in a variety of developmental processes, but little is understood about how they modulate vascular specification. A long-term goal of the applicant's laboratory is to understand how ATP-dependent chromatin-remodeling complexes epigenetically regulate transcription of genes that con- tribute to developmental and postnatal vascular pathologies, such as those that arise from misspecification of blood and lymphatic vessels. The objective of this proposal is to understand how the chromatin-remodeling enzymes BRG1 and CHD4 influence venous and lymphatic identity during embryonic development. The cen- tral hypothesis is that BRG1 and CHD4 affect venous and lymphatic identity by modulating vascular expression of the nuclear receptor Coup-TFII. This hypothesis is based on preliminary data produced in the applicant's laboratory and on phenotypic similarities between vascular Brg1, Chd4, and Coup-TFII mutant mouse em- bryos. Coup-TFII plays important roles in venous and lymphatic specification but nothing is known about what promotes its vascular expression. Therefore identification of epigenetic mechanisms for regulating its expres- sion would elucidate how COUP-TFII influences vessel development.
Two specific aims will be employed to test the central hypothesis. First, the temporal/spatial impact of BRG1 and CHD4 on venous and lymphatic identity will be discerned using an array of genetic tools. Venous and lymphatic markers in mutant embryos will be analyzed throughout development to determine precisely when and where BRG1 and CHD4 affect these vessels. Secondly, the epigenetic impact of BRG1 and CHD4 on Coup-TFII expression in veins and lymphatics will be examined. COUP-TFII expression in Brg1 and Chd4 mutants will be correlated with the ve- nous and lymphatic specification phenotypes defined in Aim 1. In addition, primary and cultured endothelial cells will be used to test the hypothesis that BRG1 and CHD4 directly promote vascular Coup-TFII expression through nucleosome remodeling and histone acetylation at the Coup-TFII promoter. The proposed research is significant because it will provide novel information about how chromatin-remodeling enzymes affect Coup-TFII expression and will serve as a first step toward developing pharmacological strategies to manipulate Coup-TFII expression in order to positively or negatively influence vascular development. This research is innovative be- cause it emphasizes epigenetic regulation of vascular development, which deviates from traditional ways of approaching this subject.
The proposed research is relevant to public health because the discovery of novel strategies for regulating Coup-TFII expression and function is expected to be therapeutically beneficial for multiple vascular pathologies, including congenital lymphatic disorders and tumors. Thus, the proposed research supports the NIH's mission of understanding fundamental developmental processes that will help reduce the burdens of human illness and disability. !
|Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126:2254-66|
|Wiley, Mandi M; Muthukumar, Vijay; Griffin, Timothy M et al. (2015) SWI/SNF chromatin-remodeling enzymes Brahma-related gene 1 (BRG1) and Brahma (BRM) are dispensable in multiple models of postnatal angiogenesis but are required for vascular integrity in infant mice. J Am Heart Assoc 4:|
|Tessneer, Kandice L; Pasula, Satish; Cai, Xiaofeng et al. (2014) Genetic reduction of vascular endothelial growth factor receptor 2 rescues aberrant angiogenesis caused by epsin deficiency. Arterioscler Thromb Vasc Biol 34:331-7|
|Chen, Hong; Griffin, Courtney; Xia, Lijun et al. (2014) Molecular and cellular mechanisms of lymphatic vascular maturation. Microvasc Res 96:16-22|
|Liu, Xiaolei; Pasula, Satish; Song, Hoogeun et al. (2014) Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal 7:ra97|
|Ingram, Kyle G; Curtis, Carol D; Silasi-Mansat, Robert et al. (2013) The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis. PLoS Genet 9:e1004031|
|Davis, Reema B; Curtis, Carol D; Griffin, Courtney T (2013) BRG1 promotes COUP-TFII expression and venous specification during embryonic vascular development. Development 140:1272-81|