Functional dissection of H3K4 methyltransferases reveals distinct catalytic and non-catalytic roles in C. elegans development.

The KMT2 class of histone methyltransferases regulates methylation of histone 3 lysine 4 (H3K4), a conserved post-translational modification associated with active transcription. However, previous studies have highlighted catalytic-independent functions of KMT2 members and questioned the influence of H3K4 methylation on gene expression. Here, we address this by generating catalytically inactive mutants of SET-2 and SET-16, the two KMT2 members in Caenorhabditis elegans. Through chromatin analysis, we determined the effect of SET-2 and SET-16 catalytic activities on H3K4me3 deposition and identified shared and distinct targets. Gene expression profiling showed that simultaneous inactivation of SET-2 and SET-16 catalytic activities results in gene deregulation independent of H3K4me3 status at transcription start sites. Finally, we examined the relevance of SET-2 and SET-16 catalytic activity on phenotypes identified in null mutants and found that SET-2 catalytic activity is essential for proper somatic development, whereas SET-16 enzymatic activity has cell type-specific roles. Interestingly, animals lacking SET-2 and SET-16 catalytic activity are viable and fertile under normal growth conditions. Our results reveal catalytic-dependent and -independent roles of KMT2 members, and that combined loss of SET-16 and SET-2 is compatible with life in C. elegans.