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DOI	10.1073/pnas.2022760118
	Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype
	Chen D.Y.; Ferguson I.M.; Braun K.A.; Sutton L.A.; Helton N.M.; Ramakrishnan S.M.; Smith A.M.; Miller C.A.; Ley T.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3AR882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin. © This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	DNA methylation; DNMT3A; Epidermis; Epigenetic; Premalignant
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179831
作者单位	Division of Dermatology, Department of Medicine, Washington University, School of Medicine, Saint Louis, MO 63110, United States; Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University, School of Medicine, Saint Louis, MO 63110, United States
推荐引用方式 GB/T 7714	Chen D.Y.,Ferguson I.M.,Braun K.A.,et al. Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype[J],2021,118(16).
APA	Chen D.Y..,Ferguson I.M..,Braun K.A..,Sutton L.A..,Helton N.M..,...&Ley T.J..(2021).Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Chen D.Y.,et al."Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).