@article{201939162f7e45ceb5381f34b94df1ab,
title = "Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells",
abstract = "Mutations 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 somatic Dnmt3a knockout mice have identified focal, canonical hypomethylation phenotypes in hematopoietic cells; however, the kinetics of methylation loss following acquired DNMT3A inactivation in hematopoietic cells is essentially unknown. Therefore, we evaluated a somatic, inducible model of hematopoietic Dnmt3a loss, and show that inactivation of Dnmt3a in 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 acquired DNMT3A mutations in hematopoietic stem cells.",
keywords = "Biological sciences, Epigenetics, Molecular biology",
author = "Smith, {Amanda M.} and Verdoni, {Angela M.} and Abel, {Haley J.} and Chen, {David Y.} and Shamika Ketkar and Leight, {Elizabeth R.} and Miller, {Christopher A.} and Ley, {Timothy J.}",
note = "Funding Information: The authors thank Ms. Mieke Hoock for excellent animal husbandry. This work was supported by an ASH Fellow to Faculty Award (A.M.S.), NIH grants CA237727 (D.Y.C.), CA211782 (C.A.M.), CA101937 and CA197561 (T.J.L.), and the Barnes-Jewish Hospital Foundation (T.J.L.). A.M.S. A.M.V. and T.J.L. designed research. A.M.S. A.M.V. D.Y.C. and E.R.L. performed research. A.M.S. H.J.A. S.K. and C.A.M. analyzed the data. A.M.S. and T.J.L. wrote the paper. A.M.S. is an employee of Incyte Corporation, A.M.V. is an employee of Vitalant Corporation, and E.R.L. is the owner of Leight Medical Communications, LLC. All studies in the manuscript were performed before the authors joined these companies. The other authors declare no competing interests. Funding Information: The authors thank Ms. Mieke Hoock for excellent animal husbandry. This work was supported by an ASH Fellow to Faculty Award (A.M.S.), NIH grants CA237727 (D.Y.C.), CA211782 (C.A.M.), CA101937 and CA197561 (T.J.L.), and the Barnes-Jewish Hospital Foundation (T.J.L.). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "15",
doi = "10.1016/j.isci.2022.104004",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
number = "4",
}