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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Ramachandran Boopathi,
  • Isabel Garcia-Saez,
  • Serhan Turunç,
  • Imtiaz Nisar Lone,
  • Ashok Kumar,
  • Abed Alkarem Abu Alhaija,
  • Jeffrey J. Hayes,
  • Jan Bednar,
  • Muhammed Kasim Diril,
  • Dimitar Iliev,
  • Anastas Gospodinov,
  • Aline Le Roy,
  • Dimitrios Skoufias,
  • Dimitar Angelov,
  • Ali Hamiche,
  • Seyit Kale,
  • Stefan Dimitrov,
  • Carlo Petosa

摘要

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.