Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions

Nat Genet. 2019 Jan;51(1):96-105. doi: 10.1038/s41588-018-0274-x.

Patricia Heyn ¹, Clare V Logan ¹, Adeline Fluteau ¹, Rachel C Challis ¹, Tatsiana Auchynnikava ², Carol-Anne Martin ¹, Joseph A Marsh ¹, Francesca Taglini ¹ ³, Fiona Kilanowski ¹, David A Parry ¹, Valerie Cormier-Daire ⁴, Chin-To Fong ⁵, Kate Gibson ⁶, Vivian Hwa ⁷, Lourdes Ibáñez ⁸ ⁹, Stephen P Robertson ¹⁰, Giorgia Sebastiani ¹¹, Juri Rappsilber ² ¹², Robin C Allshire ², Martin A M Reijns ¹, Andrew Dauber ⁷ ¹³, Duncan Sproul ¹⁴ ¹⁵, Andrew P Jackson ¹⁶

Affiliations

1 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK.
2 Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
3 Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
4 Department of Medical Genetics, INSERM UMR 1163, Université Paris-Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
5 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
6 Genetic Health Service New Zealand, Christchurch Hospital, Christchurch, New Zealand.
7 Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
8 Department of Endocrinology, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
9 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.
10 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
11 Neonatology Unit, Hospital Clinic-Maternitat, ICGON, BCNatal, University of Barcelona, Barcelona, Spain.
12 Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
13 Division of Endocrinology, Children's National Medical Center, Washington, DC, USA.
14 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK. duncan.sproul@igmm.ed.ac.uk.
15 Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK. duncan.sproul@igmm.ed.ac.uk.
16 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK. andrew.jackson@igmm.ed.ac.uk.

PMID: 30478443 DOI: 10.1038/s41588-018-0274-x

Abstract

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA Methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a^W326R pluripotent cells in vitro, and is also evident in Dnmt3a^W326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.

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