Pluto Bioinformatics

GSE143293: Histone 1 deficiency drives lymphomagenesis through disruption of 3D chromatin architecture

Bulk RNA sequencing

Linker histone H1 proteins bind to nucleosomes and cause chromatin compaction, although little is known about their biological functions. Histone H1 (HIST1H1B-E) mutations are highly recurrent in B-cell lymphomas and are present in solid tumors, but their cancer relevance and mechanism are unknown. Here we report that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. H1 mutations disrupt their ability to bind or compact chromatin. This causes profound architectural remodeling of the genome characterized by large-scale, yet focal shifts of chromatin from a compacted, to a relaxed state. The degree of decompaction results in distinct epigenetic states, primarily due to gain of histone H3 lysine 36 dimethylation, and/or loss of repressive H3K27 methylation. These changes unlock expression of stem cell genes that are normally silenced during early development. Loss of H1c and H1e alleles in mice conferred enhanced fitness and self renewal properties to germinal center B-cells, ultimately leading to aggressive lymphoma with enhanced repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We furthermore establish H1 as a bona fide tumor suppressor, whose mutation drives malignant transformation primarily through three-dimensional genome reorganization, epigenetic reprogramming and aberrant de-repression of developmentally silenced genes. SOURCE: Matt Teater (mrt2001@med.cornell.edu) - Weill Cornell Medical College