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bioRxiv · 10.64898/2026.11.12.766163

DNA Sequence Differentially Modulates Histone Core and Tail Interactions in Canonical and Centromeric Nucleosomes

Ghosh Moulick, A.·Erhardt, S.·Kozlowska, M.
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Abstract

Human centromeric chromatin is a specialized chromatin domain characterized by CENP-A-containing nucleosomes interspersed with canonical histone H3 nucleosomes. It is assembled on tandem repeats of -satellite DNA and defines centromere identity. How histone variant identity and DNA sequence jointly shape nucleosome structure and histone-DNA interactions that underpin centromeric chromatin formation remains incompletely understood. Here, we investigate the structural plasticity of the histone core and nucleosomal DNA, histone tail dynamics and DNA-sequence dependent changes for canonical (H3) and centromeric (CENP-A) nucleosomes using the SIRAH coarse-grained molecular dynamics (CG-MD) simulations. Nucleosomes containing -satellite positioning sequence (ASP) and Widom 601 DNA sequence are systematically analyzed and compared. Our simulations reveal that the centromeric nucleosome exhibits a more stable histone core with lower structural plasticity and the histone tails engage DNA differently with an overall reduction in the histone-DNA contacts compared to the canonical nucleosome. Further investigation of CENP-N binding to the CENP-A nucleosome demonstrates substantial modulation of nucleosomal DNA dynamics and histone-DNA interactions. Replacing the ASP DNA sequence with the Widom 601 sequence preserves the stability of both types of the histone core while markedly altering histone-tail dynamics. The conformational dynamics of canonical nucleosomes is more strongly affected by the Widom 601 DNA sequence than those of their centromeric counterparts. However, CENP-N binding induces more spatially extensive changes in DNA geometry in Widom 601 than in ASP DNA. Our findings suggest that DNA sequence and histone composition have residue-level differences translating into distinct nucleosome dynamics, which could be among the determinants governing the structural and dynamic properties of centromeric chromatin and its biological function.

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Ghosh Moulick, A., Erhardt, S., Kozlowska, M.. 2026-11-13. DNA Sequence Differentially Modulates Histone Core and Tail Interactions in Canonical and Centromeric Nucleosomes. https://doi.org/10.64898/2026.11.12.766163

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