A Rahman Syndrome mutation in histone H1.4 disrupts chromatin compaction and phase separation

Rahman syndrome is a rare developmental disorder caused by frameshift mutations in linker histone H1.4 that produce a truncated carboxy-terminal domain with reduced positive charge. We investigated the effects of a disease-associated mutation on chromatin structure and dynamics, focusing on H1.4-bound nucleosomes and hexanucleosomal arrays. We report that this mutation induces a more extended and flexible array conformation, characterized by enhanced linker DNA accessibility and an inability to form compact, regularly stacked nucleosome structures. Notably, mutant H1.4-bound arrays show a reduced capacity to undergo liquid-liquid and liquid-solid phase separation, closely resembling linker histone-free arrays. Molecular dynamics simulations corroborated by fluorescence resonance energy transfer measurements indicate that the mutated carboxy-terminal domain interacts with a shorter linker DNA segment, resulting in a more open nucleosome conformation. Consistent with these structural changes, the mutation significantly enhances H1.4 mobility within cell nuclei, reflecting a weaker chromatin association. The combined data suggest that Rahman syndrome-associated mutations promote an aberrantly relaxed chromatin state, potentially leading to the dysregulation of gene expression that may drive disease pathology. These findings underscore the essential role of the carboxy-terminal domain in chromatin compaction and provide mechanistic insights into the molecular etiology of Rahman syndrome.

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Publication Details

Journal
Nature Communications
Published
2026-05-22
DOI
https://doi.org/10.1038/s41467-026-73046-8
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
0.00

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article

A Rahman Syndrome mutation in histone H1.4 disrupts chromatin compaction and phase separation

Carlo Petosa, M. Kasim Diril, Jan Bednář, Ramachandran Boopathi et al.
Nature Communications
Genomics and Chromatin Dynamics
article

A Rahman Syndrome mutation in histone H1.4 disrupts chromatin compaction and phase separation

Carlo Petosa, M. Kasim Diril, Jan Bednář, Ramachandran Boopathi, Seyit Kale, Stéfan Dimitrov, Serhan Turunç, Imtiaz Nisar Lone, I. Garcia-Saez, Aline Le Roy, Abed Alkarem Abu Alhaija, Dimitar Angelov, Dimitar Iliev, Ali Hamiche, Dimitrios Skoufias, Anastas Gospodinov, Jeffrey J. Hayes, Ashok Kumar
article en

Abstract

Rahman syndrome is a rare developmental disorder caused by frameshift mutations in linker histone H1.4 that produce a truncated carboxy-terminal domain with reduced positive charge. We investigated the effects of a disease-associated mutation on chromatin structure and dynamics, focusing on H1.4-bound nucleosomes and hexanucleosomal arrays. We report that this mutation induces a more extended and flexible array conformation, characterized by enhanced linker DNA accessibility and an inability to form compact, regularly stacked nucleosome structures. Notably, mutant H1.4-bound arrays show a reduced capacity to undergo liquid-liquid and liquid-solid phase separation, closely resembling linker histone-free arrays. Molecular dynamics simulations corroborated by fluorescence resonance energy transfer measurements indicate that the mutated carboxy-terminal domain interacts with a shorter linker DNA segment, resulting in a more open nucleosome conformation. Consistent with these structural changes, the mutation significantly enhances H1.4 mobility within cell nuclei, reflecting a weaker chromatin association. The combined data suggest that Rahman syndrome-associated mutations promote an aberrantly relaxed chromatin state, potentially leading to the dysregulation of gene expression that may drive disease pathology. These findings underscore the essential role of the carboxy-terminal domain in chromatin compaction and provide mechanistic insights into the molecular etiology of Rahman syndrome.

Nature Communications
Centre National de la Recherche Scientifique (FR), Izmir University (TR), Inserm (FR), Dokuz Eylül University (TR), Bulgarian Academy of Sciences (BG), Izmir Kâtip Çelebi University (TR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), University of Rochester Medical Center (US), CEA Grenoble (FR), Institut de génétique et de biologie moléculaire et cellulaire (FR), Institute of Molecular Biology (BG), Institut de Biologie Structurale (FR), Institut pour l'avancée des biosciences (FR), Université Grenoble Alpes (FR)
European Molecular Biology Organization, Agence Nationale de la Recherche, National Institutes of Health
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Genomics and Chromatin Dynamics
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