Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin

Nucleosomes must be deacetylated behind elongating RNA polymerase II to prevent cryptic initiation of transcription within the coding region. RNA polymerase II signals for deacetylation through the methylation of histone H3 lysine 36 (H3K36), which provides the recruitment signal for the Rpd3S histone deacetylase complex (HDAC). The recognition of methyl H3K36 by Rpd3S requires the chromodomain of its Eaf3 subunit. Paradoxically, Eaf3 is also a subunit of the NuA4 acetyltransferase complex, yet NuA4 does not recognize methyl H3K36 nucleosomes. In Saccharomyces cerevisiae, we found that methyl H3K36 nucleosome recognition by Rpd3S also requires the plant homeobox domain (PHD) of its Rco1 subunit. Thus, the coupled chromo and PHD domains of Rpd3S specify recognition of the methyl H3K36 mark, demonstrating the first combinatorial domain requirement within a protein complex to read a specific histone code.