SCML2 establishes germline-specific bivalent domains.. Mus musculus

Bivalent domains marked with repressive H3K27me3 and activating H3K4me2/3 are a molecular signature of totipotency in stem cells and development. While bivalent domains are retained throughout the germline to recover totipotency in the next generation, the mechanisms establishing bivalent domains remains unknown. Here we demonstrate that a germline-specific Polycomb protein, SCML2, binds to chromatin containing hypomethylated DNA to induce H3K27me3, thereby initiating the establishment of germline-specific bivalent domains in mice. SCML2 regulates two distinct classes of autosomal bivalent domains, the first are maintained constitutively through spermatogenesis (Class I), and the second are specifically established during meiosis (Class II). In postmeiotic spermatids, the loss of H3K27me3 leads to an increase of H3K4me2/3 on bivalent domains and disorganization of pericentromic heterochromatin. We propose that SCML2 regulates dynamic bivalent domains in the germline as a molecular imprint to recover totipotency after fertilization. Overall design: ChIP-seq, ATAC-seq and RNA-seq analyses using wild-type and Scml2-KO spermatogenic cells