Catalytic-dependent and -independent functions of H3K4 methyltransferases in C. elegans development

The KMT2 class of histone methyltransferases regulates the methylation of Histone 3 Lysine 4 (H3K4), a conserved post-translational modification largely associated with active transcription. However, studies have highlighted catalytic-independent biological functions of KMT2 members and questioned the influence of H3K4 methylation on gene expression. Here, we address these questions by generating catalytic-inactive mutants of SET-2 and SET-16, the only two KMT2 members in Caenorhabditis elegans (C. elegans). By chromatin analyses we determined the effect of SET-2 and SET-16 catalytic activities on H3K4me3 deposition at regulatory elements and identified common and specific target genes. Parallel gene expression analyses indicate that lack of SET-2 and SET-16 catalytic activities results in deregulation of gene expression independent of H3K4me3 status at transcription start sites. Finally, we examinated the relevance of SET-2 and SET-16 catalytic activity on phenotypes identified in null mutants and found that the catalytic activity of SET-2 is essential for proper development and fertility, while the enzymatic activity of SET-16 has cell-type specific functions. Interestingly, animals with simultaneous loss of SET-2 and SET-16 catalytic activities are viable and fertile. Overall, our results point to catalytic-dependent and -independent roles of KMT2 members and reveal that loss of the majority of H3K4me3 is compatible with development and reproduction in C. elegans. Overall design: To investigate the enzymatic activity of SET-2 and SET-16, we generated catalytic inactive mutants of SET-2 and SET-16, set-2(zr1504) and set-16(zr1804)