Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions
| Autor: | Duncan Sproul, Lourdes Ibáñez, Robin C. Allshire, Joseph A. Marsh, Valérie Cormier-Daire, Stephen P. Robertson, Patricia C. Heyn, Andrew Dauber, Juri Rappsilber, Adeline Fluteau, Francesca Taglini, Martin A M Reijns, Giorgia Sebastiani, Andrew P. Jackson, Rachel C. Challis, Carol Anne Martin, Vivian Hwa, David A. Parry, Chin-To Fong, Fiona Kilanowski, Tatsiana Auchynnikava, Kate Gibson, Clare V. Logan |
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| Jazyk: | angličtina |
| Předmět: |
Male
Dwarfism Polycomb-Group Proteins Mice Transgenic Regulatory Sequences Nucleic Acid DNA methyltransferase Bivalent (genetics) Article DNA Methyltransferase 3A Histones 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor Genetics medicine Missense mutation Animals Humans Epigenetics DNA (Cytosine-5-)-Methyltransferases DNA Modification Methylases Cells Cultured 030304 developmental biology 0303 health sciences biology DNA Methylation medicine.disease Gain of function Histone Gain of Function Mutation DNA methylation embryonic structures biology.protein Microcephaly H3K4me3 Female 030217 neurology & neurosurgery HeLa Cells Protein Binding |
| Zdroj: | Nature genetics Heyn, P, Logan, C V, Fluteau, A, Challis, R C, Auchynnikava, T, Martin, C-A, Marsh, J A, Taglini, F, Kilanowski, F, Parry, D, Cormier-Daire, V, Fong, C-T, Gibson, K, Hwa, V, Ibanez, L, Robertson, S P, Sebastiani, G, Rappsilber, J, Allshire, R C, Reijns, M A M, Dauber, A, Sproul, D & Jackson, A P 2019, ' Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of polycomb-regulated regions ', Nature Genetics, vol. 51, no. 1, pp. 96–105 . https://doi.org/10.1038/s41588-018-0274-x NATURE GENETICS r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Nature Genetics r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/s41588-018-0274-x |
| Popis: | 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. Gain-of-function mutations altering the PWWP domain of DNMT3A are identified as a new cause of microcephalic dwarfism. These mutations abrogate DNMT3A binding to H3K36me2 and H3K36me3 and lead to aberrant DNA methylation of Polycomb-marked regions. |
| Databáze: | OpenAIRE |
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