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

During primordial germ cell (PGC) specification, repression of somatic programs is essential for the establishment of germline identity. However, mechanisms that safeguard PGC fate thereafter remain unknown. Here, we identify the E3 ubiquitin ligase TRIM37 as a critical safeguard of PGC fate during migration. Trim37 deficiency causes severe PGC defects beginning at embryonic day 9.5 (E9.5) with complete PGC depletion by E12.5, and leads to an aberrant transition toward somatic cell states. Mechanistically, TRIM37 binds TRIM28 through its MATH domain and ubiquitinates TRIM28 via its RING domain, enhancing the TRIM37-TRIM28 interaction and promoting the nuclear retention of TRIM37. Forced nuclear export of TRIM37 results in PGC loss. Moreover, disruption of TRIM37 ligase activity or mutation of TRIM28 ubiquitination sites compromises PGC maintenance. We further show that the TRIM37-TRIM28 complex, likely acting in cooperation with AP2γ, restricts chromatin accessibility and H3K27ac levels at somatic gene loci, thereby repressing somatic transcriptional programs in PGCs. Together, our findings uncover a TRIM37-TRIM28-AP2γ regulatory complex that safeguards germ cell fate by preventing the activation of somatic transcriptional programs during PGC migration.