TRIM37 interacts with TRIM28 to maintain primordial germ cell identity during migration

During embryo development, germ cells segregate from soma to ensure the genome transmission of a species. Although the repression of somatic programs in germline specification is well studied, the molecular mechanisms that protect primordial germ cell (PGC) fate thereafter remain poorly understood. Here, we show that the ubiquitin ligase TRIM37 suppresses the somatic programs during PGC migration. Trim37 mutant embryos exhibit PGC developmental defects from embryonic day 9.5 (E9.5) and depletion at E12.5, with Trim37-deficient PGCs transdifferentiating into somatic cells. Mechanistically, TRIM37 interacts with TRIM28 through its MATH domain to repress somatic gene expression in the nucleus. Forcing TRIM37 out of the nucleus causes PGC depletion. Additionally, the K27-linked polyubiquitination of TRIM28 catalyzed by TRIM37 augments their interaction and promotes the nucleus location of TRIM37. The impairment of TRIM37 ubiquitin ligase activity and mutations in TRIM28 ubiquitination sites both hinder PGC development. Furthermore, TRIM37 deficiency disrupts the DNA binding of TRIM28, which is mostly guided by AP2γ, leading to enhanced chromatin accessibility and increased H3K27ac levels, resulting in the upregulation of somatic genes. Our results shed light on the TRIM37-mediated epigenetic suppression mechanisms controlling germ cell fate maintenance and are relevant for the infertility of Mulibrey nanism patients.