Vascular Control of Organ Function
A5: The epigenetic regulator DNMT3A in endothelial beds
Epigenetic alterations play a crucial role in the control of cellular differentiation processes. In the same line, we hypothesize that the differentiation of organotypic vasculature is dependent on epigenetic control mechanisms that directly impact on organ function. Notably, epigenetic studies in angiogenesis research are still in its infancy. De novo DNA methylation, one of the best-characterized epigenetic modifications, is established, maintained and remodeled by the DNA methyltransferases DNMT3A and DNMT3B. We discovered a selective high expression of Dnmt3a in mouse endothelial cells during postnatal development (one week of age) compared to endothelial cells from adult mice (eight weeks of age), and the deletion of Dnmt3a in mice results in significantly impaired postnatal angiogenesis. Yet, the role of Dnmt3a in endothelial cell biology has only been marginally addressed so far and is unknown on a genome-wide level. Furthermore, functional consequences of Dnmt3a deletion are elusive.
This research proposal aims at identifying the role of Dnmt3a in establishing organ-specific DNA methylation landscapes in endothelial cells from different organs in vivo. Together with the corresponding Dnmt3a-dependent transcriptomes, the molecular mechanisms of organ-specific Dnmt3a function in endothelial cells will be unravelled. These omics approaches will be complemented by phenotypic and functional studies demonstrating the impact of Dnmt3a on organotypic vasculature during development, adulthood and disease. Altogether, the data from project A5 will demonstrate how endothelial cell tissue specificity is regulated by epigenetic mechanisms in general and by Dnmt3a specifically and will reveal novel epigenetic regulations of organotypic vasculature during health and disease.
Genome browser view of epigenetic modifications in endothelial cells. Depicted are differentially methylated regions (DMR) screened by WGBS (Whole Genome Bisulfite Sequencing) and chromatin accessibility (CA) screened by ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing).