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The Dnmt3L ADD Domain Controls Cytosine Methylation Establishment during Spermatogenesis

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, w...

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Detalles Bibliográficos
Autores principales: Vlachogiannis, Georgios, Niederhuth, Chad E., Tuna, Salih, Stathopoulou, Athanasia, Viiri, Keijo, de Rooij, Dirk G., Jenner, Richard G., Schmitz, Robert J., Ooi, Steen K.T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534369/
https://www.ncbi.nlm.nih.gov/pubmed/25683717
http://dx.doi.org/10.1016/j.celrep.2015.01.021
Descripción
Sumario: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.