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March 2017

Circulation. 2017 Mar 28. pii: CIRCULATIONAHA.116.026991. doi: 10.1161/CIRCULATIONAHA.116.026991.

Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function.

Leisegang MS, Fork C, Josipovic I, Richter F, Preussner J, Hu J, Miller MJ, Epah JN, Hofmann P, Günther S, Moll F, Valasarajan C, Heidler J, Ponomareva Y, Freiman TM, Maegdefessel L, Plate KH, Mittelbronn M, Uchida S, Künne C, Stellos K, Schermuly RT, Weissmann N, Devraj K, Wittig I, Boon RA, Dimmeler S, Pullamsetti SS, Looso M, Miller FJ, Brandes RP.

The endothelium forms the vascular barrier to maintain vessel function. Healthy endothelium prevents thrombus formation and inflammatory cell adhesion, whereas activated endothelium has opposing properties. Understanding how endothelial cells maintain their function is key to prevent vascular disease development. Important aspects in this regulation are epigenetic mechanisms, that control gene expression, but our understanding of vascular epigenetics is still in its beginning. Epigenetic mechanisms involve specific proteins that are able to modify the chromatin in order to regulate gene expression, but are also mediated by specific RNAs. Only a small portion of the human genome carries protein-coding potential; the majority is differentially transcribed to produce noncoding RNAs, of which the majority are long noncoding RNAs (lncRNA). Some lncRNAs are associated with epigenetic factors and possess the ability to function as an epigenetic modulator, where they recruit chromatin-modifying complexes to target sites. Therefore, lncRNAs can influence transcriptional activation or repression, depending on the interaction partner. In the present study, the authors identified the epigenetically controlled lncRNA n342419, which was named MANTIS. MANTIS possesses relevant and novel functions to maintain vessel function. Among these, the lncRNA modulates the ATPase activity of the SWI/SNF catalytic subunit BRG1 to influence the transcription of genes important for endothelial cells. They established this as a disease-relevant element controlling angiogenic function.