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

Boopathi R., Garcia-Saez I., Diril M. K., Petosa C.

NATURE COMMUNICATIONS, vol.1, no.1, pp.1, 2026 (SCI-Expanded, Scopus)

  • Publication Type: Article / Article
  • Volume: 1 Issue: 1
  • Publication Date: 2026
  • Doi Number: 10.1038/s41467-026-73046-8
  • Journal Name: NATURE COMMUNICATIONS
  • Journal Indexes: Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Health Research Premium Collection (ProQuest), Scopus, Pharma Collection (ProQuest), Technology Collection (ProQuest), Aerospace Database, Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, Chemical Abstracts Core, EMBASE, Geobase, INSPEC, MEDLINE, Directory of Open Access Journals, Zoological Record
  • Page Numbers: pp.1
  • Dokuz Eylül University Affiliated: Yes

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.