MORC3, a novel MIWI2 association partner, as an epigenetic regulator of piRNA dependent transposon silencing in male germ cells

Kanako Kojima-Kita; Satomi Kuramochi-Miyagawa; Manabu Nakayama; Haruhiko Miyata; Steven E Jacobsen; Masahito Ikawa; Haruhiko Koseki; Toru Nakano

doi:10.1038/s41598-021-98940-7

MORC3, a novel MIWI2 association partner, as an epigenetic regulator of piRNA dependent transposon silencing in male germ cells

Sci Rep. 2021 Oct 14;11(1):20472. doi: 10.1038/s41598-021-98940-7.

Authors

Kanako Kojima-Kita¹, Satomi Kuramochi-Miyagawa^{2

3}, Manabu Nakayama⁴, Haruhiko Miyata⁵, Steven E Jacobsen^{6

7

8}, Masahito Ikawa⁵, Haruhiko Koseki⁹, Toru Nakano^{10

11}

Affiliations

¹ Department of Pathology, Medical School, Osaka University, Yamada-oka 2-2 Suita, Osaka, 565-0871, Japan. kojima0208@patho.med.osaka-u.ac.jp.
² Department of Pathology, Medical School, Osaka University, Yamada-oka 2-2 Suita, Osaka, 565-0871, Japan.
³ Graduate School of Frontier Biosciences, Osaka University, Yamada-oka 2-2 Suita, Osaka, 565-0871, Japan.
⁴ Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kisarazu, Chiba, 292-0818, Japan.
⁵ Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Yamada-oka 3-1 Suita, Osaka, 565-0871, Japan.
⁶ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
⁷ Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA.
⁸ Department of Howard Hughes Medical Institute, University of California, Los Angeles, CA, 90095, USA.
⁹ RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
¹⁰ Department of Pathology, Medical School, Osaka University, Yamada-oka 2-2 Suita, Osaka, 565-0871, Japan. tnakano@patho.med.osaka-u.ac.jp.
¹¹ Graduate School of Frontier Biosciences, Osaka University, Yamada-oka 2-2 Suita, Osaka, 565-0871, Japan. tnakano@patho.med.osaka-u.ac.jp.

Abstract

The PIWI (P-element-induced wimpy testis)-interacting-RNA (piRNA) pathway plays a crucial role in the repression of TE (transposable element) expression via de novo DNA methylation in mouse embryonic male germ cells. Various proteins, including MIWI2 are involved in the process. TE silencing is ensured by piRNA-guided MIWI2 that recruits some effector proteins of the DNA methylation machinery to TE regions. However, the molecular mechanism underlying the methylation is complex and has not been fully elucidated. Here, we identified MORC3 as a novel associating partner of MIWI2 and also a nuclear effector of retrotransposon silencing via piRNA-dependent de novo DNA methylation in embryonic testis. Moreover, we show that MORC3 is important for transcription of piRNA precursors and subsequently affects piRNA production. Thus, we provide the first mechanistic insights into the role of this effector protein in the first stage of piRNA biogenesis in embryonic TE silencing mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism*
Animals
DNA Methylation / genetics*
DNA Transposable Elements
DNA-Binding Proteins / metabolism*
Epigenomics
Female
Gene Expression Regulation, Developmental*
Germ Cells / growth & development
Germ Cells / metabolism*
Male
Mice
Mice, Knockout
Mice, Transgenic
RNA, Small Interfering
Retroelements
Testis / growth & development
Testis / metabolism*

Substances

DNA Transposable Elements
DNA-Binding Proteins
RNA, Small Interfering
Retroelements
Adenosine Triphosphatases
MORC3 protein, mouse