Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex

Ganesan Senthil Kumar, William Chang, Tao Xie, Anand Patel, Yongbo Zhang, Gang Greg Wang, Gregory David, Ishwar Radhakrishnan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily conserved Rpd3S/Sin3S complex is crucial for suppressing aberrant transcription from cryptic start sites within intragenic regions of actively transcribed genes. Precise targeting of the complex relies on the chromatin binding activities of the MRG15 (MRG stands for mortality factor on chromosome 4 related gene) and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me2/3, the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here, we show that Pf1 PHD1 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me0) but not to H3K4me2/3, which are enriched in the promoter and 5′ regions of genes. Unlike previously characterized CD and PHD domains that bind to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to their targets with > 100 μM affinity, offering an explanation for why both MRG15 CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to chromatin. Our results also suggest that bivalency, rather than cooperativity, is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a biologically significant manner. Finally, the studies reveal an unanticipated role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1 MRG-binding-domain-dependent manner, implying a key role for the MRG15 MRG-Pf1 MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex.

Original languageEnglish (US)
Pages (from-to)519-531
Number of pages13
JournalJournal of Molecular Biology
Volume422
Issue number4
DOIs
StatePublished - Sep 28 2012

Keywords

  • NMR
  • combinatorial readout
  • histone code
  • histone interactions
  • transcription repression

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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