Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3S HDAC complex in C. elegans.

Flore Beurton,Alex Appert,Francesca Palladino,Ni Huang,David Cluet,Marion Herbette,Matthieu Caron,Cécile Bedet,Julie Ahringer,Yan Dong,Yohann Couté,Ron A-J Chen,Hélène Polveche,Przemyslaw Stempor,Martin Spichty

doi:10.1093/nar/gkz880

Abstract

The CFP1 CXXC zinc finger protein targets the SET1/COMPASS complex to non-methylated CpG rich promoters to implement tri-methylation of histone H3 Lys4 (H3K4me3). Although H3K4me3 is widely associated with gene expression, the effects of CFP1 loss vary, suggesting additional chromatin factors contribute to context dependent effects. Using a proteomics approach, we identified CFP1 associated proteins and an unexpected direct link between Caenorhabditis elegans CFP-1 and an Rpd3/Sin3 small (SIN3S) histone deacetylase complex. Supporting a functional connection, we find that mutants of COMPASS and SIN3 complex components genetically interact and have similar phenotypic defects including misregulation of common genes. CFP-1 directly binds SIN-3 through a region including the conserved PAH1 domain and recruits SIN-3 and the HDA-1/HDAC subunit to H3K4me3 enriched promoters. Our results reveal a novel role for CFP-1 in mediating interaction between SET1/COMPASS and a Sin3S HDAC complex at promoters.

Highlights

The CFP1/CXXC zinc finger protein targets the SET1/COMPASS complex to non-methylated CpG rich regions for trimethylation of histone H3 on Lys4 (H3K4me3) [1,2,3,4,5], a modification widely associated with active promoters [6,7,8]
We found that CFP1::GFP and HA::WDR-5.1 immunoprecipitates contained all common subunits of SET1/MLL complexes, including Swd1/RBBP-5, Bre2/ASH-2, and Sdc1/DPY-30
In this study we identify a physical and functional interaction between CFP-1, the chromatin targeting subunit of the highly conserved SET1/COMPASS complex, and a Sin3 small (SIN3S) histone deacetylase complex similar to yeast Rpd3S and mouse SHMP containing SIN-3, HDA-1, MRG-1 and ATHP-1

Summary

Introduction

The CFP1/CXXC zinc finger protein targets the SET1/COMPASS complex to non-methylated CpG rich regions for trimethylation of histone H3 on Lys (H3K4me3) [1,2,3,4,5], a modification widely associated with active promoters [6,7,8]. The roles of CFP1 and the SET1/COMPASS complex in gene regulation are unclear. The effects vary depending on context, consistent with potential interactions with other factors, and proposals that H3K4me may promote transcriptional memory and consistency [9,15,16]. The enzymatic activity of SET1/MLL family members is regulated by interactions with additional proteins, including Swd3/WDR5, Swd1/RbBP5, Bre2/ASH2 and Sdc1/hDPY30 that influence the state (mono-, di- or tri) of methylation deposited [20,21,22]. Unique subunits including CFP1 are associated with each complex and contribute to its specificity [3,23,24,25]

Methods

Results

Conclusion