POGZ suppresses 2C transcriptional program and retrotransposable elements

The POGZ gene is frequently mutated in neurodevelopmental disorders such as ASD and intellectual disability. Recent work showed POGZ is required for maintaining mouse embryonic stem cells (mESCs). However, the mechanisms were unclear. In this study, the authors demonstrate that POGZ plays a crucial role in maintenance of pluripotency by silencing 2C-like transcripts and endogenous retroviruses (ERVs) in mESCs. POGZ loss led to aberrant upregulation of the Dux gene and activation of ERVs, driving mESCs into a 2C-like state. Mechanistically, POGZ interacts with the TRIM28/SETDB1 complex to maintain repressive heterochromatin (H3K9me3/H4K20me3) at Dux and ERV loci; without POGZ, these marks are reduced and transcriptional repression fails. In vivo, loss of Pogz in mice caused embryonic lethality, and heterozygous Pogz+/– mice showed developmental delay, hyperactivity, and increased DNA damage – recapitulating features of White–Sutton syndrome. Conclusion: POGZ is an important epigenetic regulator that suppresses a 2C-like transcriptional program and transposable elements, helping maintain genome stability and normal development.