Deciphering epigenetic regulation and angiogenetic endothelial cells in health and disease
Endothelial plasticity during the angiogenic process is well accepted, however non-genetic mechanisms driving plasticity are not well studied. Gene signatures defining distinct cellular endothelial states have been extensively studied on a transcriptomic level. Yet, the underlying epigenetic mechanisms that control endothelial gene expression in healthy and diseased tissues are largely unknown. In the first funding period, the application of multi-omics techniques of pulmonary endothelial cells revealed (1) a crucial epigenetic control (DNA methylation, histone modification, nucleosome positioning) of distal regulatory genomic elements for endothelial angiogenic plasticity and (2) a tight regulation of DNA methylation patterns in regulatory genomic regions ensuring transcription factor accessibility. During lung cancer tumorigenesis the angiogenic process is re-activated. Based on our findings we hypothesize, that this re-activation coincides with epigenetic reprogramming of distal regulatory elements. Thus, in the next funding period, we propose to advance the understanding of the epigenetic control of vascular re-activation in lung cancer angiogenesis. Furthermore, we intend to understand endothelial heterogeneity on the single cell level to elucidate further on the DNA methylation-gene expression link. Anti-angiogenic therapies represent a promising therapeutic strategy. Thus, the identification of mechanisms controlling pro-angiogenic epigenetic remodeling will be of translational relevance and might represent an additional layer to target in order to interfere with cancer.