A study finds that human activity has led to a severe decrease in Caribbean shark abundance.
Image credit: Sean Mattson (International Center for Tropical Agriculture, Cali, Colombia).
Edited by Mark Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved April 1, 2014 (received for review November 28, 2013)
Significance
DNA methylation is essential for mammalian development. This modification is nearly completely erased and reestablished in early embryos, but specific classes of DNA elements escape such genome-wide changes via unknown mechanisms. In this study, we identified a likely factor responsible for lack of DNA methylation turnover on a large fraction of such sequences. By focusing on mouse embryonic stem cells depleted of de novo DNA methyltransferases, which exhibit widespread hypomethylation with the exception of particular loci, we show that regions retaining DNA methylation are associated with a specific chromatin state. In cells lacking the enzyme catalyzing this chromatin state, such regions begin to lose DNA methylation. Our results therefore advance the understanding of how DNA methylation turnover is regulated during development.
Abstract
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.
Footnotes
↵1D.L., T.D., and U.W. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: biren{at}ucsd.edu or mlorincz{at}mail.ubc.ca.
Author contributions: D.L., T.D., U.W., W.X., P.J., M.C.L., and B.R. designed research; D.L., T.D., A.Y.L., P.G., Y.L., and K.E.S. performed research; Y.L., K.E.S., and P.J. contributed new reagents/analytic tools; D.L., U.W., and W.X. analyzed data; and D.L., T.D., U.W., W.X., M.C.L., and B.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE47894).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1322273111/-/DCSupplemental.
H3K9 trimethylation inhibits DNA demethylation
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- Genetics
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