Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.,Nature Genetics

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Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.
Nature Genetics ( IF 31.7 ) Pub Date : 2018-11-26 , 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 _{1,

3} , Andrew P Jackson ₁

Affiliation

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

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.

中文翻译：

功能获得性 DNMT3A 突变导致小头侏儒症和 Polycomb 调节区域的高甲基化。

DNA 甲基化和 Polycomb 是建立脊椎动物细胞身份和命运的关键因素。在这里，我们报告了 DNMT3A 的从头错义突变，DNMT3A 编码 DNA 甲基转移酶 DNMT3A。这些突变会导致小头侏儒症，这是一种全身生长极度衰竭的细胞减少性疾病。 PWWP 结构域中的取代消除了与组蛋白修饰 H3K36me2 和 H3K36me3 的结合，并改变患者细胞中的 DNA 甲基化。多梳相关的 DNA 甲基化谷（包含发育基因的低甲基化结构域）被甲基化，同时 H3K27me3 和 H3K4me3 二价标记被耗尽。这种从头 DNA 甲基化发生在 Dnmt3aW326R 多能细胞体外分化过程中，并且在 Dnmt3aW326R/+ 侏儒小鼠中也很明显。因此，我们认为 DNMT3A PWWP 结构域与 H3K36me2 和 H3K36me3 的相互作用通常会限制 Polycomb 标记区域的 DNA 甲基化。我们的研究结果表明 DNA 甲基化和 Polycomb 在关键发育调节因子中的相互作用是哺乳动物生物体大小的决定因素。

更新日期：2019-01-25

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