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DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes

¹ Department of Pathology, Medical School, Graduate School of Frontier Biosciences, Research Institute for Microbial Diseases, Osaka University, Yamada-oka 2-2 Suita, Osaka 565-0871, Japan; ² Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Shizuoka, 411-8540, Japan; ³ Genome Annotation and Comparative Analysis Team, Computational and Experimental Systems Biology Group, RIKEN Genomic Sciences Center, Yokohama 230-0045, Japan; ⁴ Sequence Technology Team, RIKEN Genomic Sciences Center, Yokohama 230-0045, Japan; ⁵ Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Yamada-oka 2-2 Suita, Osaka 565-0871, Japan; ⁶ Laboratory of Cytogenetics, Division of Bioscience, Graduate School of Environmental Earth Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan; ⁷ Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA

Silencing of transposable elements occurs during fetal gametogenesis in males via de novo DNA methylation of their regulatory regions. The loss of MILI (miwi-like) and MIWI2 (mouse piwi 2), two mouse homologs of Drosophila Piwi, activates retrotransposon gene expression by impairing DNA methylation in the regulatory regions of the retrotransposons. However, as it is unclear whether the defective DNA methylation in the mutants is due to the impairment of de novo DNA methylation, we analyze DNA methylation and Piwi-interacting small RNA (piRNA) expression in wild-type, MILI-null, and MIWI2-null male fetal germ cells. We reveal that defective DNA methylation of the regulatory regions of the Line-1 (long interspersed nuclear elements) and IAP (intracisternal A particle) retrotransposons in the MILI-null and MIWI2-null male germ cells takes place at the level of de novo methylation. Comprehensive analysis shows that the piRNAs of fetal germ cells are distinct from those previously identified in neonatal and adult germ cells. The expression of piRNAs is reduced under MILI- and MIWI2-null conditions in fetal germ cells, although the extent of the reduction differs significantly between the two mutants. Our data strongly suggest that MILI and MIWI2 play essential roles in establishing de novo DNA methylation of retrotransposons in fetal male germ cells.

[Keywords: Piwi; piRNA; retrotransposon; DNA methylation; spermatogenesis]]

Received December 6, 2007; revised version accepted February 5, 2008.

⁹ Corresponding author.

E-MAIL tnakano{at}patho.med.osaka-u.ac.jp; FAX 81-6-6879-3729.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1640708.

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