Stage-dependent dual mechanisms of MORC2 in retrotransposon silencing and sex chromosome inactivation in germ cells.

Retrotransposon silencing and meiotic sex chromosome inactivation (MSCI) are critical for male germ cell development. MORC2, a DNA-binding ATPase, represses retrotransposons in mammalian somatic cells through association with the HUSH complex. However, the in vivo roles for MORC2 in germ cells remain unknown, as its loss leads to embryonic lethality. Here, we report two distinct functions of MORC2 during spermatogenesis. Embryonic germ cell-specific inactivation of MORC2 results in a failure in silencing of LINE1 and IAP retrotransposons in male germ cells, meiotic arrest, and male sterility. LINE1 and IAP elements are hypomethylated in MORC2-deficient testes, providing a molecular explanation for their activation. In contrast, postnatal loss of MORC2 prior to meiosis causes a failure in MSCI. Mechanistically, MORC2 binds to gene promoters and represses transcription of both autosomal and sex chromosome-linked genes through H3K9me3 deposition in meiotic cells with a preferential effect on sex chromosome-linked genes. Biochemically, MORC2 interacts with MORC1 and SETDB1 in testis. Our results demonstrate that MORC2 plays stage-dependent dual functions in male germ cells: retrotransposon silencing in pre-meiotic cells and MSCI in meiotic cells, through association with MORC1 and SETDB1, respectively.