文章基本信息

标题：Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells
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作者：Amanda M. Smith ; Angela M. Verdoni ; Haley J. Abel 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：4
页码：1-18
DOI：10.1016/j.isci.2022.104004
语种：English
出版社：Elsevier
摘要：SummaryMutations in the gene encoding DNA methyltransferase 3A (DNMT3A) are the most common cause of clonal hematopoiesis and are among the most common initiating events of acute myeloid leukemia (AML). Studies in germline and somaticDnmt3aknockout mice have identified focal, canonical hypomethylation phenotypes in hematopoietic cells; however, the kinetics of methylation loss following acquiredDNMT3Ainactivation in hematopoietic cells is essentially unknown. Therefore, we evaluated a somatic, inducible model of hematopoieticDnmt3aloss, and show that inactivation ofDnmt3ain murine hematopoietic cells results in a relatively slow loss of methylation at canonical sites throughout the genome; in contrast, remethylation of Dnmt3a deficient genomes in hematopoietic cells occurs much more quickly. This data suggests that slow methylation loss may contribute, at least in part, to the long latent period that characterizes clonal expansion and leukemia development in individuals with acquiredDNMT3Amutations in hematopoietic stem cells.Graphical abstractDisplay OmittedHighlights•Somatic inactivation ofDnmt3ain hematopoietic cells causes slow DNA methylation loss•Methylation loss occurs in an ordered fashion, at canonical sites in the genome•Many genomic regions that lose or gain methylation rapidly are overlapping•Methylation remodeling is an integrated process involving methylases and demethylasesBiological sciences; Molecular biology; Epigenetics