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Published on: November 29, 2016
WDR-5 exhibits H3K4 methylation-independent activity during embryonic development in C. elegans
Nurulhafizah Binti Samsudin1, Siyao Wang2, Kate Fisher1
1Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Background:
Histone H3 lysine 4 methylation (H3K4me) is generally associated with active transcription and bivalent chromatin but can also contribute to repression. In metazoans, H3K4 methylation is catalysed by KMT2 methyltransferases assembled with the core scaffolding proteins WDR5, ASH2L, and RBBP5. RBBP5 mediates complex assembly and nucleosome binding, whilst WDR5 stabilises interactions to promote tri-methylation. However, WDR5 also exhibits additional moonlighting functions, leaving its specific roles in H3K4 methylation and transcription regulation unclear. Using C. elegans embryos, spike-in ChIP-seq, and null alleles of wdr-5(-) and rbbp-5(-), we dissected the contributions of these scaffolds towards H3K4 mono-, di-, and tri-methylation as well as gene expression during C. elegans embryogenesis.
Results:
We show that C. elegans RBBP-5 is essential for both mono- and multi-methylated H3K4 deposition. On the other hand, WDR-5 is primarily required for H3K4me3, but can influence H3K4me2 and H3K4me1 deposition either positively or negatively depending on the genomic feature involved. We additionally performed RNA-seq on these mutants and found that rbbp-5 deletion was largely tolerated with mis-regulation of ~ 700 genes, whereas the wdr-5 deletion led to widespread transcriptomic disruption (~ 3000 genes). We initially hypothesised that these broad changes were driven by the altered H3K4me1/me2 landscape in the wdr-5(-) mutant. However, transcriptomic profiling of the wdr-5(-); rbbp-5(-) double mutant, which lacks H3K4 methylation, revealed a high degree of similarity to the wdr-5(-) single mutant. This refuted our initial hypothesis and indicated that the changes in H3K4 methylation are unlikely to underlie the transcriptional effects of the wdr-5 deletion.
Conclusions:
Our findings support the notion that WDR-5 profoundly shapes gene expression through RBBP-5-independent mechanisms and possibly beyond H3K4 methylation. Distinguishing between H3K4me-dependent and independent functions of WDR-5 will further understanding of its roles in development and disease.
