---
title: "Single-residue changes in the nucleosome core identify a regulatory hub for phenotypic innovation"
id: "biorxiv-12-single-residue-variation-in-the-nucleosome-core-reveals-a-regulatory-hub-for"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-12-single-residue-variation-in-the-nucleosome-core-reveals-a-regulatory-hub-for"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.11.750863v1?rss=1"
published_at: "2026-09-13T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Single-residue changes in the nucleosome core identify a regulatory hub for phenotypic innovation
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-12-single-residue-variation-in-the-nucleosome-core-reveals-a-regulatory-hub-for
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.11.750863v1?rss=1)
- **Published At:** 2026-09-13T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study maps how single-residue variation in the six-residue loop 2 (L2) of histone variants **H2A** and **H2A.Z** alters cellular function at single-residue resolution. - Genome-scale interaction mapping revealed hundreds of regulatory connections that extend beyond chromatin to include **actin organization**, endocytosis, and membrane trafficking. - Interactions were both **residue-specific** and different between the H2A and H2A.Z paralogues, indicating a finely encoded regulatory landscape by single amino acids. - Transcriptome profiling showed limited changes in gene expression and little overlap between differentially expressed genes and the identified regulatory partners, suggesting non-chromatin connections are not explained by transcriptional changes alone. - Substitutions in the L2 loop preferentially conferred fitness benefits under cell wall and membrane stress, linking nucleosome variation to peripheral cellular phenotypes. - The findings support a model in which the **nucleosome** and histone variation act as sources of phenotypic innovation beyond canonical chromatin regulation. - Funding sources and administrative notes reported include the FWF Austrian Science Fund, EMBO, and the Gregor Mendel Institute; two authors are co-inventors on a related patent filed by the Gregor Mendel Institute. - The full experimental details, quantitative interaction lists, and supplementary materials are available in the preprint; specific experimental methods and numeric results beyond the summary were not fully reported in the abstract alone.
## Clinical Analysis & Structured Key Points
Single-residue variation in the nucleosome core reveals a regulatory hub for phenotypic innovation | bioRxiv Skip to main content New Results Single-residue variation in the nucleosome core reveals a regulatory hub for phenotypic innovation View ORCID Profile Zachary H Harvey , Benjamin Gundinger , View ORCID Profile Jian Yi Kok , Kathryn M Stevens , View ORCID Profile Tobias Warnecke , View ORCID Profile Frederic Berger doi: https://doi.org/10.64898/2026.09.11.750863 Zachary H Harvey 1 Gregor Mendel Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Zachary H Harvey For correspondence: zachary.harvey{at}gmi.oeaw.ac.at Benjamin Gundinger 1 Gregor Mendel Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jian Yi Kok 1 Gregor Mendel Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jian Yi Kok Kathryn M Stevens 2 MRC Laboratory of Medical Sciences; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tobias Warnecke 3 University of Oxford Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tobias Warnecke Frederic Berger 1 Gregor Mendel Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Frederic Berger Abstract Info/History Metrics Supplementary material Preview PDF Abstract Nucleosomes organize genomes and regulate DNA access, yet accumulating evidence suggests that their constituent histones may have functions beyond canonical chromatin regulation, but the breadth of such regulatory diversity remains unclear. Here, we used the six-residue loop 2 (L2) of H2A and H2A.Z to map, at single-residue resolution, how nucleosome-core variation reshapes cellular function. Genome-scale interaction mapping identified hundreds of regulatory connections spanning chromatin, as well as actin organization, endocytosis, and membrane trafficking. Interactions were residue-specific and differed between H2A and H2A.Z, revealing a regulatory landscape encoded by single residues. Transcriptome profiling showed limited expression changes and little overlap between differentially expressed genes and regulatory partners, indicating that non-chromatin connections are not readily explained by altered transcription. L2 substitutions also preferentially conferred benefits under cell wall and membrane stress. Thus, the nucleosome is linked to cellular-periphery functions beyond classical chromatin regulation, identifying histone variation as a source of phenotypic innovation. Competing Interest Statement F.B. and Z.H.H. are co-inventors on a patent filed by the Gregor Mendel Institute (European Patent WO2025233441A1). Funder Information Declared FWF Austrian Science Fund, https://ror.org/013tf3c58 , TAI304 , ESP213B European Molecular Biology Organization, https://ror.org/04wfr2810 , ALTF169-2020 Gregor Mendel Institute of Molecular Plant Biology, https://ror.org/05twjp994 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 13, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Single-residue variation in the nucleosome core reveals a regulatory hub for phenotypic innovation Zachary H Harvey , Benjamin Gundinger , Jian Yi Kok , Kathryn M Stevens , Tobias Warnecke , Frederic Berger bioRxiv 2026.09.11.750863; doi: https://doi.org/10.64898/2026.09.11.750863 Share This Article: Copy Citation Tools Single-residue variation in the nucleosome core reveals a regulatory hub for phenotypic innovation Zachary H Harvey , Benjamin Gundinger , Jian Yi Kok , Kathryn M Stevens , Tobias Warnecke , Frederic Berger bioRxiv 2026.09.11.750863; doi: https://doi.org/10.64898/2026.09.11.750863 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7983) Biochemistry (18684) Bioengineering (14804) Bioinformatics (44278) Biophysics (22531) Cancer Biology (19650) Cell Biology (26810) Clinical Trials (138) Developmental Biology (13915) Ecology (20940) Epidemiology (2067) Evolutionary Biology (25400) Genetics (16132) Genomics (23443) Immunology (18640) Microbiology (42360) Molecular Biology (17992) Neuroscience (93155) Paleontology (695) Pathology (2974) Pharmacology and Toxicology (5075) Physiology (8087) Plant Biology (15944) Scientific Communication and Education (2094) Synthetic Biology (4546) Systems Biology (10202) Zoology (2381)
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