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bioRxiv · 10.1101/442699

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Espinosa-Diez, C.·Wilson, R.·Mukherjee, R.·Feltham, M.·Hudson, C.·Ruhl, R.·Anand, S.
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Abstract

Changes in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

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Espinosa-Diez, C., Wilson, R., Mukherjee, R., Feltham, M., Hudson, C., Ruhl, R., Anand, S.. 2018-10-14. DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9. https://doi.org/10.1101/442699

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