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Epigenetic Control of Microsomal Prostaglandin E Synthase-1 by HDAC Mediated Recruitment of p300

: Fork, C.; Vasconez, A.E.; Janetzko, P.; Angioni, C.; Schreiber, Y.; Ferreiros, N.; Geisslinger, G.; Leisegang, M.S.; Steinhilber, D.; Brandes, R.P.


Journal of lipid research 58 (2016), Nr.2, 386-392
ISSN: 0022-2275
ISSN: 1539-7262
Fraunhofer IME ()

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medicine to treat pain, fever, inflammation and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. Inhibition of HDACs (HDACi) with the pan HDAC inhibitor SAHA attenuated prostaglandin E2 (PGE2) generation in the murine vasculature and in human vascular smooth muscle cells. Interestingly, other prostanoids were not changed. In line with this, the expression of the key enzyme for PGE2 synthesis, microsomal prostaglandin E synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-Seq analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. Conclusion: HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.