Journal
CELL REPORTS
Volume 10, Issue 6, Pages 944-956Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.01.021
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Funding
- BBSRC David Phillips Fellowship [BB/H022546/1]
- ERC Starting Grant [2817840, 311704]
- NIH [R00GM100000]
- Biotechnology and Biological Sciences Research Council [BB/H022546/1] Funding Source: researchfish
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1402183] Funding Source: National Science Foundation
- European Research Council (ERC) [311704] Funding Source: European Research Council (ERC)
- BBSRC [BB/H022546/1] Funding Source: UKRI
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A critical aspect of mammalian gametogenesis is the reprogramming of genomic DNA methylation. The catalytically inactive adaptor Dnmt3L is essential to ensuring this occurs correctly, but the mechanism by which it functions is unclear. Using gene targeting to engineer a single-amino-acid mutation, we show that the Dnmt3L histone H3 binding domain (ADD) is necessary for spermatogenesis. Genome-wide single-base-resolution DNA methylome analysis of mutant germ cells revealed overall reductions in CG methylation at repetitive sequences and non-promoter CpG islands. Strikingly, we also observe an even more severe loss of non-CG methylation, suggesting an unexpected role for the ADD in this process. These epigenetic deficiencies were coupled with defects in spermatogonia, with mutant cells displaying marked changes in gene expression and reactivation of retrotransposons. Our results demonstrate that the Dnmt3L ADD is necessary for Dnmt3L function and full reproductive fitness.
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