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bioRxiv · 10.64898/2026.11.04.764309

An expanded evolutionary landscape of H3 histones with variants that destabilize nucleosomes and promote chromatin accessibility

Rivera-Lopez, C. F.·Nosella, M. L.·Jena, S. G.·Bump, P.·Duncan, E.·Buenrostro, J. D.·Luger, K.·Srivastava, M.
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Abstract

Histones are among the most conserved proteins in eukaryotes, yet many animal lineages have evolved divergent histone variants with specialized functions. Some broadly conserved variants (e.g., H3.3) have been linked to the regulation of chromatin accessibility in stem cells, but whether highly divergent variants function similarly remains unclear. Here, we characterize the histone repertoire of the acoel Hofstenia miamia, an animal that can undergo whole-body regeneration using adult pluripotent stem cells (aPSCs). We identify two novel histone H3 paralogs, H3-a and H3-b, that are expressed in aPSCs and form a lineage-specific sister clade to H3.2 and H3.3. Despite substantial sequence divergence and reduced compatibility with canonical chaperone machinery, both variants assemble bona fide nucleosomes in vitro. These nucleosomes exhibit reduced stability and incomplete DNA wrapping, and a cryo-EM structure of the H3-b nucleosome reveals the disruption of conserved histone-DNA contacts. In vivo, H3-a and H3-b are upregulated following injury, and their depletion reduces genome-wide chromatin accessibility, suggesting a role in the maintenance of accessible chromatin during regeneration. A survey of H3 sequences across animal phyla shows that H3-a and H3-b belong to a broader landscape of highly divergent H3 proteins, some of which exhibit sequence differences across both the N-terminal tail and histone-fold domain. Together, these findings link histone sequence diversification to chromatin regulation in aPSCs and highlight the underappreciated evolutionary diversity and functional potential of divergent animal H3 proteins.

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Rivera-Lopez, C. F., Nosella, M. L., Jena, S. G., Bump, P., Duncan, E., Buenrostro, J. D., Luger, K., Srivastava, M.. 2026-11-06. An expanded evolutionary landscape of H3 histones with variants that destabilize nucleosomes and promote chromatin accessibility. https://doi.org/10.64898/2026.11.04.764309

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