H1 histones control the epigenetic landscape by local chromatin compaction

Area of Science:

• Molecular Biology
• Epigenetics
• Genomics

Background:

• Linker histones H1 are abundant chromatin proteins crucial for nucleosome spacing and chromatin folding.
• In vivo functions of H1 linker histones remain largely uncharacterized.
• Understanding H1's role is key to deciphering chromatin structure and gene regulation.

Purpose of the Study:

• To investigate the in vivo role of H1 linker histones in controlling chromatin compaction and gene expression.
• To elucidate the mechanisms by which H1 influences the epigenetic landscape and 3D genome organization.

Main Methods:

• Generation of a conditional triple-H1-knockout mouse strain.
• Depletion of H1 in hematopoietic cells, specifically T cells.
• Chromatin structure analysis using chromosome conformation capture (Hi-C).
• Assessment of histone methylation marks (H3K27, H3K36) and gene expression.

Main Results:

• H1 depletion in T cells de-represses T cell activation genes, mimicking normal activation.
• H1-mediated compaction is localized to genomic regions with high H1 density, including Hi-C B compartments and PRC2-marked A compartments.
• Reduced H1 stoichiometry alters epigenetic marks (decreased H3K27me3, increased H3K36me3) and shifts Hi-C compartments.
• In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation via chromatin compaction.

Conclusions:

• Local H1 density regulates the balance between repressive and active chromatin domains through genomic compaction.
• H1 is a critical regulator of gene silencing by controlling chromatin compaction, 3D genome organization, and the epigenetic landscape.
• These findings provide mechanistic insights into H1's role in establishing and maintaining epigenetic states.