Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1

Proc Natl Acad Sci U S A. 2014 May 6;111(18):6690-5. doi: 10.1073/pnas.1322273111. Epub 2014 Apr 22.


During mammalian development, DNA methylation patterns need to be reset in primordial germ cells (PGCs) and preimplantation embryos. However, many LTR retrotransposons and imprinted genes are impervious to such global epigenetic reprogramming via hitherto undefined mechanisms. Here, we report that a subset of such genomic regions are resistant to widespread erasure of DNA methylation in mouse embryonic stem cells (mESCs) lacking the de novo DNA methyltransferases (Dnmts) Dnmt3a and Dnmt3b. Intriguingly, these loci are enriched for H3K9me3 in mESCs, implicating this mark in DNA methylation homeostasis. Indeed, deletion of the H3K9 methyltransferase SET domain bifurcated 1 (Setdb1) results in reduced H3K9me3 and DNA methylation levels at specific loci, concomitant with increased 5-hydroxymethylation (5hmC) and ten-eleven translocation 1 binding. Taken together, these data reveal that Setdb1 promotes the persistence of DNA methylation in mESCs, likely reflecting one mechanism by which DNA methylation is maintained at LTR retrotransposons and imprinted genes during developmental stages when DNA methylation is reprogrammed.

Keywords: 5-hydroxymethylcytosine; epigenomics; histone modifications; repetitive elements.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation* / genetics
  • DNA Methyltransferase 3A
  • DNA Methyltransferase 3B
  • Embryonic Stem Cells / metabolism
  • Endogenous Retroviruses / genetics
  • Endogenous Retroviruses / metabolism
  • Epigenesis, Genetic
  • Female
  • Genomic Imprinting*
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / chemistry
  • Histones / genetics
  • Histones / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Retroelements / genetics*


  • Dnmt3a protein, mouse
  • Histones
  • Retroelements
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, mouse

Associated data

  • GEO/GSE47894