Transcriptional mechanisms that regulate endothelial cell (EC) lineage identity and homeostasis are essential for vascular health. The ETS transcription factor (TF) ERG is a master regulator of endothelial homeostasis, EC lineage specification and angiogenesis. ERG co-operates with other transcription factors and co-activators to regulate transcription. ERG drives expression of homeostatic genes whilst repressing pro-inflammatory and pro-endothelial-to-mesenchymal transition (EndMT) genes, by binding to regulatory elements such as promoters and enhancers. ERG-bound enhancers drive the expression of EC-specific genes and can define super-enhancers in human umbilical vein EC (HUVEC). ERG-bound enhancers and super-enhancers are enriched for genetic variants most strongly associated with cardiovascular disease traits (CVD); whether any of these variants functionally affect regulation of EC-specific genes is unknown. In this thesis, I explored how ERG controls transcriptional and epigenetic mechanisms to maintain EC homeostasis. I showed that a CVD-associated variant located in an ERG super-enhancer of the LDLR gene has allele-specific effects on enhancer activity. I also demonstrated that ERG and GATA2 may co-operate to drive this enhancer. Using immunoprecipitation and mass spectrometry, I dissected how ERG forms EC transcriptional networks by studying ERG binding partners in HUVEC. I identified that ERG forms protein-protein interactions with other TFs, splicing factors, co-regulators, and chromatin remodellers. Specifically, I showed that ERG co-purified with several chromatin remodellers, including the Brahma associated factor complex (BAF) subunit, Brahma related gene 1 (BRG1; SMARCA4). I then investigated ERG’s relationship with BRG1 in mediating EC gene regulation. I showed that ERG-dependent regulation of EC transcription is partially mediated by BRG1. ERG and BRG1 co-operated at specific genomic loci to regulate gene expression, while at other loci, they competed. Globally, ERG and BRG1 co-operate more frequently to repress gene expression. Finally, the role of another BAF subunit, Brahma (BRM; SMARCA2) in ERG and BRG1 mediated gene regulation was studied. I and a Randi lab group member showed that BRM was required to compensate for the depletion of BRG1 at selected genes related to EndMT. Studies into how ERG forms transcriptional networks in EC will provide greater insight into the molecular mechanisms maintaining EC homeostasis.