Unknown,Transcriptomics,Genomics,Proteomics

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WDR-5 exhibits H3K4 methylation-independent activity, whereas RBBP-5 is essential for H3K4 methylation during embryonic development in C. elegans

ABSTRACT: Enrichment in the deposition of methyl groups at Histone 3 lysine 4 (H3K4) is associated with active transcription and bivalent chromatin. In yeast, there is evidence additionally supporting a role in repression during stress, In metazoans, H3K4 methylation levels are controlled by a conserved scaffold complex comprised of WDR5, ASH2L, and RBBP5 acting in association with one of the many H3K4 methyltransferases available. RBBP5 facilitates the assembly of the complex and association with the nucleosome. WDR5 coordinates the interaction between RBBP5 and the enzyme to facilitate methylation. WDR5 has moonlighting activities and is found in additional complexes, raising questions about WDR-5’s specific role in H3K4 methylation. Using the C. elegans embryo system coupled with spike-in ChIP-seq and null alleles for wdr-5 and rbbp-5, we defined the impact that these two scaffolding components have on the deposition of H3K4 mono-, di-, and tri-methylation and on gene expression.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Caenorhabditis elegans

SUBMITTER: Leo Zeef

PROVIDER: E-MTAB-15080 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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 and H3K4me2 landscapes 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 indicates that the changes in H3K4 methylation are unlikely to underlie the transcriptional effects of the wdr-5 deletion. Conclusions:Our findings strongly indicate that WDR-5 profoundly shapes gene expression through mechanisms beyond H3K4 methylation. Distinguishing between H3K4me-dependent and independent functions of WDR-5 will further understanding of its roles in development and disease.

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WDR-5 exhibits H3K4 methylation-independent activity, whereas RBBP-5 is essential for H3K4 methylation during embryonic development in C. elegans

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