Cancer mutations rewire linker histone interaction network and compromise chromatosome stability

Area of Science:

• Molecular Biology
• Genomics
• Structural Biology

Background:

• Histone H1 is crucial for higher-order chromatin organization and nucleosome stability.
• Cancer-associated mutations in Histone H1 can disrupt its architectural role.

Purpose of the Study:

• To investigate how cancer-associated mutations affect Histone H1's interaction network and chromatin structure.
• To elucidate the mechanistic basis of H1 mutations in genome dysregulation.

Main Methods:

• Construction of a comprehensive H1-centered interaction network using structural and crosslinking mass spectrometry data.
• Mapping cancer mutations onto the network to identify affected interfaces and PTM sites.
• Molecular dynamics simulations to assess the impact of mutations on chromatosome stability and dynamics.

Main Results:

• Cancer mutations are enriched at protein-protein interfaces and PTM sites within the H1 network, suggesting disruption of histone modification crosstalk.
• Mutations affecting linker DNA binding cause modest perturbations, while the S104F mutation significantly destabilizes the chromatosome by disrupting hydrogen bonds and increasing flexibility.
• The study links network topology with atomic-level dynamics to explain mutation effects.

Conclusions:

• Histone H1 mutations rewire chromatin interactions and destabilize nucleosome architecture through distinct mechanisms.
• Understanding these mechanisms provides insight into oncohistone-driven genome dysregulation in cancer.
• This work advances knowledge of how structural perturbations in Histone H1 contribute to cancer development.