Unraveling the Role of TET3 in regulating EndMT in Cardiac Fibrosis

Maamari, Sabine

dc.contributor.advisor	Zeisberg, Elisabeth Prof. Dr.
dc.contributor.author	Maamari, Sabine
dc.date.accessioned	2023-02-10T16:07:41Z
dc.date.available	2023-12-15T00:50:09Z
dc.date.issued	2023-02-10
dc.identifier.uri	http://resolver.sub.uni-goettingen.de/purl?ediss-11858/14509
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-9696
dc.format.extent	129 Seiten	de
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/
dc.subject.ddc	610	de
dc.title	Unraveling the Role of TET3 in regulating EndMT in Cardiac Fibrosis	de
dc.type	doctoralThesis	de
dc.contributor.referee	Zelarayán, Laura C. PD Dr.
dc.date.examination	2022-12-16	de
dc.description.abstracteng	DNA 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.	de
dc.contributor.coReferee	Katschinski, Dörthe Prof. Dr.
dc.contributor.thirdReferee	Dressel, Ralf Prof. Dr.
dc.contributor.thirdReferee	Wollnik, Bernd Prof. Dr.
dc.contributor.thirdReferee	Papantonis, Argyris Prof. Dr.
dc.subject.eng	Cardiac fibrosis	de
dc.subject.eng	EndMT	de
dc.subject.eng	TET3	de
dc.subject.eng	miR-30d	de
dc.identifier.urn	urn:nbn:de:gbv:7-ediss-14509-8
dc.affiliation.institute	Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.description.embargoed	2023-12-15	de
dc.identifier.ppn	1834181917
dc.identifier.orcid	0000-0002-3901-1650	de
dc.notes.confirmationsent	Confirmation sent 2023-02-13T06:15:01	de

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Das Dokument erscheint in:

GGNB - Göttinger Graduiertenzentrum für Neurowissenschaften, Biophysik und molekulare Biowissenschaften [1115]
GGNB - Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences

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