DNMT3B PWWP mutations cause hypermethylation of heterochromatin.

DNA Methylation Epigenetics Heterochromatin

Journal

EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049

Informations de publication

Date de publication:
30 Jan 2024
Historique:
received: 18 04 2023
accepted: 21 12 2023
revised: 21 12 2023
medline: 31 1 2024
pubmed: 31 1 2024
entrez: 30 1 2024
Statut: aheadofprint

Résumé

The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein's N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome.

Identifiants

pubmed: 38291337
doi: 10.1038/s44319-024-00061-5
pii: 10.1038/s44319-024-00061-5
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Wellcome Trust
ID : 210493
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203149
Pays : United Kingdom

Informations de copyright

© 2024. The Author(s).

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Auteurs

Francesca Taglini (F)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Ioannis Kafetzopoulos (I)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Altos Labs, Cambridge Institute, Cambridge, UK.

Willow Rolls (W)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.

Kamila Irena Musialik (KI)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
MRC London Institute of Medical Sciences and Institute of Clinical Sciences, Imperial College London, London, UK.

Heng Yang Lee (HY)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Endocrine Oncology Research Group, Department of Surgery, The Royal College of Surgeons RCSI, University of Medicine and Health Sciences, Dublin, Ireland.

Yujie Zhang (Y)

Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.

Mattia Marenda (M)

IEO, European Institute of Oncology IRCCS, Department of Experimental Oncology, Milan, Italy.

Lyndsay Kerr (L)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK.

Hannah Finan (H)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Swiss Federal Institute of Technology, ETH Zürich, Institute of Molecular Health Sciences, Zürich, Switzerland.

Cristina Rubio-Ramon (C)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.

Philippe Gautier (P)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Hannah Wapenaar (H)

Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.

Dhananjay Kumar (D)

Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.

Hazel Davidson-Smith (H)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Jimi Wills (J)

CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Laura C Murphy (LC)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Ann Wheeler (A)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Marcus D Wilson (MD)

Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK. Marcus.Wilson@ed.ac.uk.

Duncan Sproul (D)

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. d.sproul@ed.ac.uk.
CRUK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. d.sproul@ed.ac.uk.

Classifications MeSH