Relationship between PIWIL4-Mediated H3K4me2 Demethylation and piRNA-Dependent DNA Methylation

Abstract

Summary: Retrotransposon genes are silenced by DNA methylation because of potential harm due to insertional mutagenesis. DNA methylation of retrotransposon genes is erased and re-established during male germ cell development. Both piRNA-dependent and piRNA-independent mechanisms are active during the re-establishment process, with the piRNA-independent mechanism occurring first. In this study, we analyzed the role of PIWIL4/MIWI2 in the modification of histone H3 and subsequent piRNA-dependent DNA methylation. Dimethylation at H3K4 is highly enriched at piRNA-dependent methylated regions and anti-correlated with de novo DNA methylation during the phase of piRNA-independent DNA methylation. In addition, PIWIL4, which binds the H3K4 demethylases KDM1A and KDM5B, is required for removing H3K4me2 marks. These data show that PIWIL4 plays important roles in histone modification and piRNA-dependent DNA methylation. : Nagamori et al. report that H3K4me2 is enriched at piRNA-dependent regions, such as LINE1s/L1s, in embryonic germ cells. H3K4me2 is subsequently erased in a PIWIL4-dependent manner. They postulate that preferential interaction of PIWIL4 with KDM1A and KDM5B plays a critical role in PIWIL4-dependent methylation erasure. Keywords: germ cell, spermatogenesis, DNA methylation, piRNA, gonocyte