Project Summary
Uncovering the role of a new DNA sequence pattern in nucleosome–protein interactions
How transcription factors (TFs) interact with nucleosomes has been a subject under intensive research in
chromosome biology. Most studies so far are focused on TFs to understand how they recognize their binding
motifs in a nucleosome. Very few work, however, has investigated the role of their binding partner, nucleosomal
DNA, in the interaction. Nucleosomal DNA sequences exhibit a well-known ~10-bp periodic pattern of WW/SS
dinucleotides (where W is adenine or thymine and S is guanine or cytosine). WW dimers tend to occur at the
sites where nucleosomal DNA bends into minor grooves facing toward the histones core, whereas SS dimers
are often positioned at the sites where nucleosomal DNA bends into major grooves facing toward the core.
Structurally, conserved ‘sprocket’ arginine residues from histones insert into the minor-groove bending sites
(minor-GBS) where WW dinucleotides are enriched. Because short A/T stretches have narrowed minor grooves,
there is a favorable interaction between the negatively charged DNA backbone and the positively charged
arginine residues. Recently, we found that nucleosomes with an opposite pattern, anti-WW/SS pattern, are
widespread across eukaryotic genomes. Anti-WW/SS nucleosomes tend to have SS (instead of WW)
dinucleotides at the minor-GBS, which are thought to have a weakened interaction with the arginine residues.
However, it remains unclear whether nucleosomes with the anti-WW/SS pattern indeed have less favorable
histone-DNA contacts and how this unusual pattern influences TF binding in chromatin. In Aim 1, we will leverage
existing genomic data to elucidate the sequence basis for nucleosome depleted regions over TF-bound genomic
sites. In Aim 2, we will examine and compare histone-DNA contacts for fragments of DNA in WW/SS
nucleosomes and anti-WW/SS nucleosomes using molecular dynamics simulation. At the end of the project, we
should have clarified the role of the anti-WW/SS pattern in the histone-DNA and nucleosome-TF interactions as
compared to the common WW/SS pattern, which will provide novel mechanistic insights into these interactions.