Unraveling the Role of TET3 in regulating EndMT in Cardiac FibrosisDoctoral thesis
Date of Examination:2022-12-16
Date of issue:2023-02-10
Advisor:Prof. Dr. Elisabeth Zeisberg
Referee:PD Dr. Laura C. Zelarayán
Referee:Prof. Dr. Dörthe Katschinski
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Bernd Wollnik
Referee:Prof. Dr. Argyris Papantonis
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EnglishDNA methylation and subsequent silencing of gene expression is associated with disease states including tumorigenesis and fibrosis. Although DNA methylation is a dynamic and reversible process, the mechanisms of and requirements for reactivation of gene expression via demethylation are relatively unknown. We have previously identified endothelial to mesenchymal transition (EndMT) as an important contributor to cardiac fibrosis, and TET3 as an enzyme capable of rescuing the expression of fibrosis suppressor genes such as Rasal1, in kidney and cardiac fibrosis via reversing aberrant promoter methylation. In this thesis, we used a newly generated endothelial Tet3 knockout mouse model and demonstrate both elevated EndMT markers expression and increased cardiac fibrosis in these mice. We further provide evidence that TET3 is an upstream regulator of the cardioprotective miRNA, miR-30d, which inhibits the EndMT transcription factor Snail. Moreover, employing Rasal1 as a model gene to decipher the mechanism of site-specific demethylation, we here identified that a novel lncRNA termed Gm15749 located at the promoter of Rasal1 forms an R-loop and thereby mediates specific recruitment of the active demethylation complex involving TET3 and GADD45G to Rasal1. In summary, our results demonstrate several independent antifibrotic mechanisms of TET3 on a molecular level, proposing induction of TET3 and/or induction of its downstream targets as potential new therapeutic options to treat cardiac fibrosis.
Keywords: Cardiac fibrosis; EndMT; TET3; miR-30d