Dnmt1 has de novo activity targeted to transposable elements

Chuck Haggerty; Helene Kretzmer; Christina Riemenschneider; Abhishek Sampath Kumar; Alexandra L Mattei; Nina Bailly; Judith Gottfreund; Pay Giesselmann; Raha Weigert; Björn Brändl; Pascal Giehr; René Buschow; Christina Galonska; Ferdinand von Meyenn; Melissa B Pappalardi; Michael T McCabe; Lars Wittler; Claudia Giesecke-Thiel; Thorsten Mielke; David Meierhofer; Bernd Timmermann; Franz-Josef Müller; Jörn Walter; Alexander Meissner

doi:10.1038/s41594-021-00603-8

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. Epub 2021 Jun 17.

Authors

Chuck Haggerty^#^{1

2}, Helene Kretzmer^#¹, Christina Riemenschneider^{1

3}, Abhishek Sampath Kumar¹, Alexandra L Mattei^{1

4

5}, Nina Bailly¹, Judith Gottfreund⁶, Pay Giesselmann¹, Raha Weigert^{1

3}, Björn Brändl^{1

7}, Pascal Giehr⁸, René Buschow⁹, Christina Galonska^{1

10}, Ferdinand von Meyenn⁸, Melissa B Pappalardi¹¹, Michael T McCabe¹¹, Lars Wittler¹², Claudia Giesecke-Thiel¹³, Thorsten Mielke⁹, David Meierhofer¹⁴, Bernd Timmermann¹⁵, Franz-Josef Müller^{1

7}, Jörn Walter⁶, 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.

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.

Publication types

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

MeSH terms

Animals
CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism
Cells, Cultured
Chromatin / metabolism
DNA (Cytosine-5-)-Methyltransferase 1 / genetics
DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methylation / genetics*
DNA Methyltransferase 3A
DNA Methyltransferase 3B
DNA Transposable Elements / genetics*
Embryonic Development / genetics*
Gene Knockout Techniques
Genome / genetics
Histones / metabolism
Mice
Mouse Embryonic Stem Cells / cytology
Tripartite Motif-Containing Protein 28 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Whole Genome Sequencing

Substances

CCAAT-Enhancer-Binding Proteins
Chromatin
DNA Transposable Elements
Histones
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A
Dnmt1 protein, mouse
Trim28 protein, mouse
Tripartite Motif-Containing Protein 28
Ubiquitin-Protein Ligases
Uhrf1 protein, mouse

Associated data

figshare/10.6084/m9.figshare.14555250