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Stolz, P.* ; Mantero, A.S.* ; Tvardovskiy, A. ; Ugur, E.* ; Wange, L.E.* ; Mulholland, C.B.* ; Cheng, Y.* ; Wierer, M.* ; Enard, W.* ; Schneider, R. ; Bartke, T. ; Leonhardt, H.* ; Elsässer, S.J.* ; Bultmann, S.*

TET1 regulates gene expression and repression of endogenous retroviruses independent of DNA demethylation.

Nucleic Acids Res. 50, 8491-8511 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
DNA methylation (5-methylcytosine (5mC)) is critical for genome stability and transcriptional regulation in mammals. The discovery that ten-eleven translocation (TET) proteins catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized our perspective on the complexity and regulation of DNA modifications. However, to what extent the regulatory functions of TET1 can be attributed to its catalytic activity remains unclear. Here, we use genome engineering and quantitative multi-omics approaches to dissect the precise catalytic vs. non-catalytic functions of TET1 in murine embryonic stem cells (mESCs). Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. In particular, we show that TET1 is critical for the establishment of H3K9me3 and H4K20me3 at endogenous retroviral elements (ERVs) and their silencing that is independent of its canonical role in DNA demethylation. Furthermore, we provide evidence that this repression of ERVs depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Journal Nucleic Acids Research
Quellenangaben Volume: 50, Issue: 15, Pages: 8491-8511 Article Number: , Supplement: ,
Publisher Oxford University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
Grants Helmholtz Gesellschaft
Cyliax foundation