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


Journal

Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011

Informations de publication

Date de publication:
26 08 2022
Historique:
accepted: 20 07 2022
revised: 25 04 2022
received: 11 10 2021
pubmed: 30 7 2022
medline: 30 8 2022
entrez: 29 7 2022
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 35904814
pii: 6651872
doi: 10.1093/nar/gkac642
pmc: PMC9410877
doi:

Substances chimiques

DNA-Binding Proteins 0
Proto-Oncogene Proteins 0
TET1 protein, mouse 0
5-Methylcytosine 6R795CQT4H
Cytosine 8J337D1HZY

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

8491-8511

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Auteurs

Paul Stolz (P)

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Munich 81377, Germany.

Angelo Salazar Mantero (AS)

Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet 17165 Stockholm, Sweden, Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet 17177 Stockholm, Sweden.

Andrey Tvardovskiy (A)

Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Enes Ugur (E)

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Munich 81377, Germany.
Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany.

Lucas E Wange (LE)

Faculty of Biology, Anthropology and Human Genomics, Ludwig-Maximilians-Universität München 82152, Planegg-Martinsried, Germany.

Christopher B Mulholland (CB)

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Munich 81377, Germany.

Yuying Cheng (Y)

Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet 17165 Stockholm, Sweden, Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet 17177 Stockholm, Sweden.

Michael Wierer (M)

Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried 82152, Germany.

Wolfgang Enard (W)

Faculty of Biology, Anthropology and Human Genomics, Ludwig-Maximilians-Universität München 82152, Planegg-Martinsried, Germany.

Robert Schneider (R)

Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Till Bartke (T)

Institute of Functional Epigenetics (IFE), Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Heinrich Leonhardt (H)

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Munich 81377, Germany.

Simon J Elsässer (SJ)

Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet 17165 Stockholm, Sweden, Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet 17177 Stockholm, Sweden.

Sebastian Bultmann (S)

Faculty of Biology and Center for Molecular Biosystems (BioSysM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Munich 81377, Germany.

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