Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction(1), although their biological functions are poorly understood. Histone H1 (HIST1H1B-E) mutations are highly recurrent in B-cell lymphomas, but their cancer relevance and mechanism are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in profound architectural remodeling of the genome characterized by large-scale, yet focal shifts of chromatin from a compacted, to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily due to gain of histone H3 lysine 36 dimethylation, and/or loss of repressive H3 lysine 27 trimethylation. 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, followed by epigenetic reprogramming and derepression of developmentally silenced genes.