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Nat Struct Mol Biol. 2018 May;25(5):394-404. doi: 10.1038/s41594-018-0058-0. Epub 2018 Apr 30.

Defective germline reprogramming rewires the spermatogonial transcriptome.

Author information

1
MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
2
European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
3
Epigenetics Programme, Babraham Institute, Cambridge, UK.
4
Wellcome Trust Sanger Institute, Hinxton, UK.
5
European Bioinformatics Institute, Hinxton, UK.
6
MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh, UK. donal.ocarroll@ed.ac.uk.
7
European Molecular Biology Laboratory (EMBL), Monterotondo, Italy. donal.ocarroll@ed.ac.uk.

Abstract

Defective germline reprogramming in Piwil4 (Miwi2)- and Dnmt3l-deficient mice results in the failure to reestablish transposon silencing, meiotic arrest and progressive loss of spermatogonia. Here we sought to understand the molecular basis for this spermatogonial dysfunction. Through a combination of imaging, conditional genetics and transcriptome analysis, we demonstrate that germ cell elimination in the respective mutants arises as a result of defective de novo genome methylation during reprogramming rather than because of a function for the respective factors within spermatogonia. In both Miwi2-/- and Dnmt3l-/- spermatogonia, the intracisternal-A particle (IAP) family of endogenous retroviruses is derepressed, but, in contrast to meiotic cells, DNA damage is not observed. Instead, we find that unmethylated IAP promoters rewire the spermatogonial transcriptome by driving expression of neighboring genes. Finally, spermatogonial numbers, proliferation and differentiation are altered in Miwi2-/- and Dnmt3l-/- mice. In summary, defective reprogramming deregulates the spermatogonial transcriptome and may underlie spermatogonial dysfunction.

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