Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Abstract

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.

Deciphering the Complexity of 3D Chromatin Organization Driving Lymphopoiesis and Lymphoid Malignancies

“…Loss of H1 either in B or T lymphocytes was also shown to induce a profound reprogramming of epigenetic states with an expansion of H3K36me2 deposition at the expense of H3K27me3, suggesting that H1 binding plays an active role in balancing these modifications (203). Deletion of H1c and H1e in murine GC B cells conferred enhanced fitness and self-renewal, while at the molecular level inducing large-scale, but focal, chromatic decompaction and de-repression of stemness signature gene (202). Accordingly, Hi-C analysis revealed thousands of B-to-A compartment switches, which mostly represented expansion of A compartments, coinciding with spreading of H3K36me2.…”

“…Dynamic changes in chromatin state may also induce 3D architectural changes either through the differential affinity between homotypic or heterotypic histone modifications or through protein-protein interactions among the recruited epigenetic readers (121,123,129,199,200). Although, literature has mainly focused on core histones and their modifications, two recent studies started shedding light into the role of H1 linker histones in local and global chromatin architecture, in the context of B and T cell biology (201,202). Using a triple conditional knock out (cTKO) for Histone 1 isoforms c/d/e, Willcockson et al specifically depleted H1 in murine T-cells and uncovered a de-repression of T-cell activation genes along with chromatin decompaction, reminiscent of T-cell activation.…”

Human B Lymphomas Reveal Their Secrets Through Genetic Mouse Models

“…Heterozygous H1 mutations, found in up to 44% of FL and 27% of GCB-DLBCL, are mostly missense events affecting the globular C-terminal domain which led to the loss of protein function with impaired chromatin binding (53). Among them, H1C and H1E are the most common affected H1 isoforms observed in B cell lymphomas (102,103).…”

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape

“…Distinct from mutations, altered epigenetic status, i.e., chromosomal conditions that influence gene expression without changing the primary DNA sequence, plays an important role in the development of B-cell lymphomas [25][26][27]. Variable epigenetic components throughout the genome that influence gene expression include DNA methylation and patterns of histone modification, which alter chromatin structure, DNA accessibility and gene expression patterns [28].…”