SUMO-mediated regulation of a H3K4me3 reader controls germline development in C. elegans

Abstract

ULP-2 is a conserved SUMO protease required for embryonic development in C. elegans. Here we revealed that ULP-2 controls germline development by regulating the PHD-SET domain protein, SET-26. Specifically, the ulp-2 mutant hermaphrodites exhibit increased sterility and progressive elevation in global protein sumoylation. In the progeny of homozygous animals, meiosis is arrested at the diplotene stage and the cells in the proximal germline acquire a somatic fate. Germline RNAseq analysis revealed the downregulation of numerous germline genes, whereas somatic gene expression is upregulated in ulp-2 mutant gonads. To determine the key factors that are regulated by ULP-2, we performed a yeast two-hybrid screen and identified the H3K4me3 reader, SET-26. Genetic interaction was observed in double mutant ulp-2;set-26 resulting in enhanced sterility phenotype to complete sterility in the first generation of homozygous offspring. Consistently, SET-26 is sumoylated and its sumoylation levels are regulated by ULP-2. Moreover, we detected reduction in H3K4me3 levels bound to SET-26 in the ulp-2 mutant background. A comparative proteomics screen between WT and ulp-2 loss of activity identified the predicted methyltransferase SET-27 as a ULP-2-dependent SET-26-associated protein. SET-27 knockout genetically interacts with ULP-2 in the germline, but not with SET-26. Taken together, we revealed a ULP-2/SET-26 axis which is required for the maintenance and regulation of germline development.