Rapid and accurate remethylation of DNA in Dnmt3a- deficient hematopoietic cells with restoration of DNMT3A activity

Author:

Li Yang1ORCID,Abel Haley J.1ORCID,Cai Michelle1ORCID,LaValle Taylor A.1ORCID,Yin Tiankai1ORCID,Helton Nichole M.1ORCID,Smith Amanda M.1ORCID,Miller Christopher A.1ORCID,Ley Timothy J.1ORCID

Affiliation:

1. Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.

Abstract

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of Dnmt3a or Dnmt3b (or both enzymes) or expressing the dominant-negative Dnmt3a R878H mutation [R882H in humans; the most common DNMT3A mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive “chaperone” for DNMT3A and DNMT3B in early embryogenesis). Overexpression of DNMT3A for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3a R878H/+ marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.

Publisher

American Association for the Advancement of Science (AAAS)

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