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, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. These genetic 'gain-of-function' mutations directly contrast previously reported haploinsufficiency mutations causing a macrocephalic overgrowth disorder, Tatton-Brown Rahman syndrome.
Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3 and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/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 H3K36me2/3 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.