Dnmt1 has de novo activity targeted to transposable elements

Nat Struct Mol Biol. 2021 Jul;28(7):594-603. doi: 10.1038/s41594-021-00603-8.

Chuck Haggerty ^# ¹ ², Helene Kretzmer ^# ¹, Christina Riemenschneider ¹ ³, Abhishek Sampath Kumar ¹, Alexandra L Mattei ¹ ⁴ ⁵, Nina Bailly ¹, Judith Gottfreund ⁶, Pay Giesselmann ¹, Raha Weigert ¹ ³, Björn Brändl ¹ ⁷, Pascal Giehr ⁸, René Buschow ⁹, Christina Galonska ¹ ¹⁰, Ferdinand von Meyenn ⁸, Melissa B Pappalardi ¹¹, Michael T McCabe ¹¹, Lars Wittler ¹², Claudia Giesecke-Thiel ¹³, Thorsten Mielke ⁹, David Meierhofer ¹⁴, Bernd Timmermann ¹⁵, Franz-Josef Müller ¹ ⁷, Jörn Walter ⁶, Alexander Meissner ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
2 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
3 Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
5 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
6 Department of Genetics and Epigenetics, Saarland University, Saarbrücken, Germany.
7 Christian-Albrechts-Universität zu Kiel, Department of Psychiatry and Psychotherapy, Kiel, Germany.
8 Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
9 Microscopy and Cryo-electron Microscopy Service Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
10 Spatial Transcriptomics, Part of 10x Genomics Inc, Stockholm, Sweden.
11 Epigenetics Research Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.
12 Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
13 Flow Cytometry Joint Facilities Scientific Service, Max Planck Institute for Molecular Genetics, Berlin, Germany.
14 Mass Spectrometry Joint Facilities Scientific Service, Max Planck Institute for Molecular Genetics, Berlin, Germany.
15 Sequencing Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany.
16 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany. [email protected].
17 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany. [email protected].
18 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. [email protected].
19 Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
# Contributed equally.

PMID: 34140676 DOI: 10.1038/s41594-021-00603-8

Abstract

DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical maintenance enzyme DNMT1 and the de novo Dnmts, 3a and 3b. Here, we demonstrate that DNMT1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore Sequencing in genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that the de novo methylation activity of DNMT1 depends on UHRF1, and its genomic recruitment overlaps with regions that enrich for UHRF1, Trim28 and H3K9 trimethylation. Our data demonstrate that DNMT1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.

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