Abstract
Histone 1 (H1) deficiency altered chromatin architecture to enable transcription of stemness genes.
Major Finding: Histone 1 (H1) deficiency altered chromatin architecture to enable transcription of stemness genes.
Concept: H1 mutations, common in B-cell lymphomas, increased lymphoma aggressiveness and self-renewal in vivo.
Impact: This work suggests that H1 is a true driver of lymphomagenesis and supports an epigenetic mechanism.
B-cell lymphomas commonly harbor mutations in genes encoding isoforms of histone 1 (H1), but it is not clear whether these mutations are true drivers or, if so, how they contribute to lymphomagenesis. Yusufova and colleagues found that mice in which the orthologs of the most commonly mutated H1 isoform–encoding genes in human B-cell lymphomas were knocked out (H1c−/−H1e−/− mice) had a greater number of germinal centers (GC), and these GCs were enlarged. H1c−/−H1e−/− GC B cells, specifically centrocytes (the nondividing B cells in the light zone of a GC), had a competitive advantage in mouse bone marrow relative to wild-type (WT) GC B cells. RNA-sequencing analyses revealed that the transcriptomic profile of H1c−/−H1e−/− GC B cells differed markedly from that of WT GC B cells; specifically, the H1-deficient H1c−/−H1e−/− GC B cells exhibited relative upregulation of stemness-associated genes. Chromatin conformation capture experiments demonstrated that H1 deficiency in H1c−/−H1e−/− GC B cells caused differences in chromatin architecture that primarily manifested as decompaction of thousands of discrete chromatin domains, with hundreds of these domains making complete shifts from compartment-B (strongly compacted and transcriptionally silenced) to compartment-A (open, transcriptionally poised or active) chromatin. Notably, many of the genomic regions that shifted from highly compacted, inactive states to open, active states included stemness-related genes upregulated in H1-deficient H1c−/−H1e−/− GC B cells. Additionally, the regions that adopted active, compartment-A chromatin states in H1c−/−H1e−/− GC B cells were characterized by an increase in dimethylation of histone 3 at lysine residue 36 (H3K36me2, a marker of active chromatin) and, in some cases, a reduction in H3K27me3 (a marker of inactive chromatin). In a mouse model of diffuse large B-cell lymphoma, loss of H1c and H1e conferred increased disease aggressiveness and enhanced the self-renewal capabilities of GC B cells. In summary, this work supplies evidence that mutations affecting H1 isoforms may be true drivers of B-cell lymphomas and elucidates a mechanism explaining this phenomenon.
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