MIWI2 as an Effector of DNA Methylation and Gene Silencing in Embryonic Male Germ Cells
Kanako Kojima-Kita,
Satomi Kuramochi-Miyagawa,
Ippei Nagamori,
Narumi Ogonuki,
Atsuo Ogura,
Hidetoshi Hasuwa,
Takashi Akazawa,
Norimitsu Inoue,
Toru Nakano
Affiliations
Kanako Kojima-Kita
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Satomi Kuramochi-Miyagawa
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Ippei Nagamori
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Narumi Ogonuki
RIKEN BioResources Center, Tsukuba 305-0074, Ibaraki, Japan
Atsuo Ogura
RIKEN BioResources Center, Tsukuba 305-0074, Ibaraki, Japan
Hidetoshi Hasuwa
Department of Experimental Genome Research, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Takashi Akazawa
Department of Tumor Immunology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan
Norimitsu Inoue
Department of Tumor Immunology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan
Toru Nakano
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
During the development of mammalian embryonic germ cells, global demethylation and de novo DNA methylation take place. In mouse embryonic germ cells, two PIWI family proteins, MILI and MIWI2, are essential for the de novo DNA methylation of retrotransposons, presumably through PIWI-interacting RNAs (piRNAs). Although piRNA-associated MIWI2 has been reported to play critical roles in the process, its molecular mechanisms have remained unclear. To identify the mechanism, transgenic mice were produced; they contained a fusion protein of MIWI2 and a zinc finger (ZF) that recognized the promoter region of a type A LINE-1 gene. The ZF-MIWI2 fusion protein brought about DNA methylation, suppression of the type A LINE-1 gene, and a partial rescue of the impaired spermatogenesis of MILI-null mice. In addition, ZF-MIWI2 was associated with the proteins involved in DNA methylation. These data indicate that MIWI2 functions as an effector of de novo DNA methylation of the retrotransposon.
