Abstract

Nucleosomal DNA has a well-documented periodic pattern known as Weak Weak/Strong Strong (WW/SS where W is A or T and S is G or C) in which WW dinucleotides preferentially occur at DNA sites that bend into minor grooves whereas SS dinucleotides are often found at sites that bend into major grooves. Recent studies found that an opposite pattern named the anti-WW/SS pattern runs inverse to the WW/SS pattern and is thought to have unfavorable histone-DNA interactions. The anti-WW/SS pattern is widespread in eukaryotic genomes and enriched in mammalian genes. Whether this unusual sequence pattern has an impact on the interaction between nucleosomes and transcription factors (TFs) remains unclear. We hypothesize that anti-WW/SS nucleosomes are enriched around transcription factor binding sites. To test this, we developed two software pipelines to analyze the binding sites of 739 TFs across human and mouse cell lines. We calculated change in nucleosome positional score (ΔNPS values, the difference in the fractions of WW/SS and anti-WW/SS nucleosomes) and compared these with in vivo nucleosome occupancy profiles around TF binding sites. This analysis revealed five distinct modes of nucleosome-TF interactions: AMBIGUOUS, DIP/PEAK, DIP/DIP, PEAK/PEAK, and PEAK/DIP. These profile groups were conserved between human and mouse, indicating evolutionarily conserved modes of nucleosome-TF interaction. We performed protein domain analysis using the NCBI Conserved Domain Database to annotate DNA-binding domains and compared our classifications with Taipale et al. (2018), achieving 98.6% concordance. The most frequent domains were bHLH and bZIP, followed by Homeodomain, Forkhead, and zf-C2H2. HLH was enriched in the DIP/PEAK group and Forkhead in the DIP/DIP group. We mapped 71 TFs onto Taipale's binding preference data and found that TFs with end preference were predominantly in the DIP/DIP group, consistent with FOXA family binding behavior. Statistical comparison of 20 pioneer factors with regular TFs revealed no significant difference in profile pattern distributions, suggesting that pioneer activity may depend more on contextual edge binding at nucleosome entry/exit sites than on intrinsic nucleosome strength at the motif. Implications for nucleosome rotational positioning and pioneer factor function are discussed.

Publication Date

3-3-2026

Document Type

Thesis

Student Type

Graduate

Degree Name

Bioinformatics (MS)

Department, Program, or Center

Thomas H. Gosnell School of Life Sciences

College

College of Science

Advisor

Feng Cui

Advisor/Committee Member

Gary Skuse

Advisor/Committee Member

Emiliano Brini

Additional Files
Supplementary Tables.xlsx (151 kB)

Campus

RIT – Main Campus

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