The KRAB-Zinc finger protein ZFP708 mediates epigenetic repression at RMER19B retrotransposons

ABSTRACT Global epigenetic reprogrammingis vital to purge germ cell-specific epigenetic features to establish the totipotentstate of the embryo. This process transpires to be carefully regulated and is not an undirected, radical erasure of parental epigenomes. The TRIM28complex has been shown to be crucial in embryonic epigenetic reprogrammingby regionally opposing DNA demethylationto preserve vital parental information to be inherited from germline to soma. Yet the DNA-binding factors guiding this complex to specific targets are largely unknown. Here, we uncover and characterize a novel, maternally expressed, TRIM28-interacting KRAB zinc-finger protein: ZFP708. It recruits the repressive TRIM28complex to RMER19B retrotransposonsto evoke regional heterochromatinformation. ZFP708 binding to these hitherto unknown TRIM28targets is DNA methylation and H3K9me3 independent. ZFP708 mutant mice are viable and fertile, yet embryos fail to inherit and maintain DNA methylation at ZFP708 target sites. This can result in activation of RMER19B-adjacent genes, while ectopic expressionof ZFP708 results in transcriptional repression. Finally, we describe the evolutionary conservation of ZFP708 in mice and rats, which is linked to the conserved presence of the targeted RMER19B retrotransposonsin these species.