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H1 linker histones regulate the balance of repressive and active chromatin domains via localized genomic compaction [ATAC-seq]

ABSTRACT: H1 linker histones are the most abundant chromatin binding proteins. Their association with chromatin determines the spacing between nucleosomes and enables arrays of nucleosomes to fold into more compact chromatin structures. Mammals express multiple H1 proteins and are able to compensate for the loss of one or even two members by increasing synthesis of other members to maintain a constant H1 to nucleosome stoichiometry. To study the role of H1 in mammalian development, we generated a conditional triple H1 knockout (H1cTKO) mouse strain that enables depletion of H1 in specific cell types. Here, we report on the effects of depleting H1 in adult hematopoietic cells. Deletion of the genes encoding three widely expressed H1 subtypes (H1c, H1d, and H1e) has particularly profound effects on B- and T- lymphocyte development. H1 depletion leads to de-repression of T-cell activation genes, and a shift in T-cells towards effector functions, a process that mimics normal T-cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T-cells revealed that H1 binding produces localized chromatin compaction within spatially defined chromatin domains containing above average levels of H1. Reduction of H1 stoichiometry in these regions leads to decreases in H3K27 methylation and increases in H3K36 methylation. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. These findings identify H1 as a critical regulator of the epigenetic landscape in mammalian cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE141184 | GEO | 2020/09/09

REPOSITORIES: GEO

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H1 linker histones regulate the balance of repressive and active chromatin domains via localized genomic compaction [Hi-C]

Project description:H1 linker histones are the most abundant chromatin binding proteins. Their association with chromatin determines the spacing between nucleosomes and enables arrays of nucleosomes to fold into more compact chromatin structures. Mammals express multiple H1 proteins and are able to compensate for the loss of one or even two members by increasing synthesis of other members to maintain a constant H1 to nucleosome stoichiometry. To study the role of H1 in mammalian development, we generated a conditional triple H1 knockout (H1cTKO) mouse strain that enables depletion of H1 in specific cell types. Here, we report on the effects of depleting H1 in adult hematopoietic cells. Deletion of the genes encoding three widely expressed H1 subtypes (H1c, H1d, and H1e) has particularly profound effects on B- and T- lymphocyte development. H1 depletion leads to de-repression of T-cell activation genes, and a shift in T-cells towards effector functions, a process that mimics normal T-cell activation. Comparison of chromatin structure in normal and H1-depleted CD8+ T-cells revealed that H1 binding produces localized chromatin compaction within spatially defined chromatin domains containing above average levels of H1. Reduction of H1 stoichiometry in these regions leads to decreases in H3K27 methylation and increases in H3K36 methylation. In vitro, H1 promotes PRC2-mediated H3K27 methylation and inhibits NSD2-mediated H3K36 methylation. Mechanistically, H1 mediates these opposite effects by promoting physical compaction of the chromatin substrate. These findings identify H1 as a critical regulator of the epigenetic landscape in mammalian cells.

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

Project description: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.

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