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Estrogen-related receptors (ERRs) have emerged as major metabolic regulators in various tissues. However, their expression and function in the vasculature remains unknown. Here we report the transcriptional program and cellular function of ERRα in endothelial cells (ECs), a cell type with a multi-faceted role in vasculature. Of the three ERR subtypes ECs exclusively express ERRα. Gene expression profiling of ECs lacking ERRα revealed that ERRα predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration and cell adhesion. ERRα-deficient ECs exhibit decreased proliferation, but increased migration and tube formation. ERRα depletion increased basal, VEGFA and ANG1/2 stimulated angiogenic sprouting in endothelial spheroids. Moreover, retinal angiogenesis is enhanced in ERRα knockout mice compared to wild type mice. Surprisingly, ERRα is dispensable for the regulation of its classic targets such as metabolism, mitochondrial biogenesis and cellular respiration in the ECs. ERRα is enriched at the promoters of angiogenic, migratory and cell adhesion genes. Further, VEGFA increased ERRα recruitment to angiogenesis-associated genes and simultaneously decreased their expression. Despite increasing its gene occupancy, pro-angiogenic stimuli decrease ERRα expression in ECs. Our work shows that endothelial ERRα plays a repressive role in angiogenesis, and potentially fine-tunes growth factor-mediated angiogenesis. [ABSTRACT FROM AUTHOR]

Cotranscriptional recruitment of pre-mRNA splicing factors to their genomic targets facilitates efficient and ordered assembly of a mature messenger ribonucleoprotein particle (mRNP). However, how the cotranscriptional recruitment of splicing factors is regulated remains largely unknown. Here, we demonstrate that protein arginine methylation plays a novel role in regulating this process in Saccharomyces cerevisiae. Our data show that Hmt1, the major type I arginine methyltransferase, methylates Snp1, a U1 small nuclear RNP (snRNP)-specific protein, and that the mammalian Snp1 homolog, U1-70K, is likewise arginine methylated. Genome-wide localization analysis reveals that the deletion of the HMT1 gene deregulates the recruitment of U1 snRNP and its associated components to intron-containing genes (ICGs). In the same context, splicing factors acting downstream of U1 snRNP addition bind to a reduced number of ICGs. Quantitative measurement of the abundance of spliced target transcripts shows that these changes in recruitment result in an increase in the splicing efficiency of developmentally regulated mRNAs. We also show that in the absence of either Hmt1 or of its catalytic activity, an association between Snp1 and the SR-like protein Npl3 is substantially increased. Together, these data support a model whereby arginine methylation modulates dynamic associations between SR-like protein and pre-mRNA splicing factor to promote target specificity in splicing. [ABSTRACT FROM AUTHOR]