Condensation of an H3K9me3 methyltransferase complex promotes heritable gene silencing and heterochromatin formation

Histone H3K9 trimethylation (H3K9me3) contributes to the establishment and maintenance of heterochromatin and heritable gene silencing. H3K9me3 preferentially deposited at repetitive sequence regions, although the underlying mechanism remains poorly understood. Here, we identify SECP-1 and SECP-2 as cofactors for genome-wide H3K9me3 deposition in Caenorhabditis elegans. SECP-1 directly interacts with both SECP-2 and the H3K9me3 methyltransferase SET-25, forming a protein complex that bridges SECP-2 and SET-25. This complex assembles in the cytoplasm and enters the nucleus via SET-25. Once in the nucleus, the complex is recruited to and concentrated at SET-25 genomic targets in an interdependent manner. The accumulation of this complex correlates with condensate formation at repetitive sequences, perinuclear heterochromatin localization, and the inheritance of small RNA-mediated gene silencing. We propose that repetitive sequences drive the formation of condensates containing H3K9me3 methyltransferase complexes, resulting in preferential H3K9me3 deposition at these genomic regions.