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 H3K36me(2/3), 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 
(H3K4me(0)) but not to H3K4me(2/3), 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.