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

Patricia Heyn, Clare V. Logan, Adeline Fluteau, Rachel C. Challis, Tatsiana Auchynnikava, Carol-Anne Martin, Joseph A. Marsh, Francesca Taglini, F. Kilanowski, David Parry, Valerie Cormier-Daire, Chin-To Fong, Kate Gibson, Vivian Hwa, Lourdes Ibanez, Stephen P Robertson, Giorgia Sebastiani, Juri Rappsilber, Robin C. Allshire, Martin A. M. ReijnsAndrew Dauber, Duncan Sproul, Andrew P. Jackson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ 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.
Original languageEnglish
Pages (from-to)96–105
Number of pages10
JournalNature Genetics
Issue number1
Early online date26 Nov 2018
Publication statusPublished - Jan 2019


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