MIWI2 as an Effector of DNA Methylation and Gene Silencing in Embryonic Male Germ Cells.
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.
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Kanako
K
Kojima-Kita
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; CREST, Japan Science and Technology Agency.
Satomi
S
Kuramochi-Miyagawa
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Ippei
I
Nagamori
RIKEN BioResources Center, Tsukuba 305-0074, Ibaraki, Japan.
Narumi
N
Ogonuki
RIKEN BioResources Center, Tsukuba 305-0074, Ibaraki, Japan.
Atsuo
A
Ogura
Department of Experimental Genome Research, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hidetoshi
H
Hasuwa
Department of Tumor Immunology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan.
Takashi
T
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
N
Inoue
Department of Pathology, Medical School, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; CREST, Japan Science and Technology Agency. Electronic address: tnakano@patho.med.osaka-u.ac.jp.
Toru
T
Nakano
D000595:Amino Acid Sequence; D000818:Animals; D060565:Argonaute Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D019175:DNA Methylation / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013091:Spermatogenesis; D013094:Spermatozoa / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000378:metabolism; D016335:Zinc Fingers
D060565:Argonaute Proteins; C546575:PIWIL4 protein, mouse; D034741:RNA, Small Interfering; D012319:RNA Polymerase II