Sunday, May 11, 2025
5/11/2025
Uncovering the role of a new DNA sequence pattern in nucleosome-protein interactions - 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 regions. 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.
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