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

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: GSE152176 | 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 [CUT&Tag]

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.

2020-09-09 | GSE153543 | GEO

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

2020-09-09 | GSE141186 | GEO

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

2020-09-09 | GSE141185 | GEO

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

2020-09-09 | GSE141184 | GEO

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.

2020-09-02 | GSE143293 | GEO

Histone post translational modification mass sprectrometry SUZ12 exon 4 cell lines

Project description:We investigate the contribution of each SUZ12 isoform on PRC2 activity on chromatin using our different ESC lines. As an additional comparison for ∆ex4 cells (SUZ12-S), we included an ESC clone in which an unsuccessful CRISPR editing event resulted in a mutant allele with nearly constitutive splicing of exon 4 (herein, CSex4) and normal Suz12 expression levels (expressing only SUZ12-L). First, we profiled H3K27 bulk PTMs by WB and observed that, while CSex4 cells showed no major differences to control cells, ∆ex4 cells displayed lower levels of H3K27me2 and -me3, with higher levels of mono-methylation and acetylation. Similar results were obtained when comparing SUZ12-L and SUZ12-S ESC rescue lines. To validate these findings with an antibody-independent technique, and to additionally profile other histone PTMs, we analysed these cells with histone-MS. In line with the previous estimates26, WT cells displayed approximately 85% of H3K27 methylation. This proportion was largely similar in CSex4 cells, while it dropped to ~50% in ∆ex4 cells, with H3K27me2 and -me3 being the most affected modifications. Notably, H3K27me2/3 loss in ∆ex4 cells occurred at histone peptides regardless of their H3K36 methylation status. Moreover, the global H3K36 methylation rates were not affected in either CSex4 or ∆ex4 cells (Figure S4C), and no major changes in methylation or acetylation levels were observed at other residues. Importantly, reintroduction of SUZ12-L in KO cells rescued a higher degree of methylation compared to SUZ12-S. Overall, these results indicate that SUZ12-S alone is unable to maintain global physiological levels of H3K27 methylation; rather SUZ12-L is also necessary for this task.

2024-03-18 | PXD046640 | Pride

Local states of chromatin compaction in HepG2 cells

Project description:We reported chromatin compaction states within several nucleosomes in HepG2 cells. To assess the local compaction, fromaldehyde-treated chromatin was appled to fractionation via a sedimentation velocity cetrifugation. While less-crosslinked nucleosomes remained in upper fractions as open chromatin, well-crosslinked nucleosomes were sedimented to lower fractions as compact chromatin.

2020-03-10 | GSE146632 | GEO

Chromatin immunoprecipitation of wild type, SET2 deletion, Rco1 PHD domain deletion and Eaf3 chromodomain deletion yeast using anti-acetyl-histone H4

Project description:Nucleosomes must be deacetylated behind elongating RNA polymerase II to prevent cryptic initiation of transcription within the coding region. RNA polymerase II signals for deacetylation through methylation of histone H3 lysine 36 (H3K36) which provides the recruitment signal for the Rpd3S deacetylase complex. Recognition of methyl-H3K36 by Rpd3S requires the chromodomain of its Eaf3 subunit. Paradoxically, Eaf3 is also a subunit of the NuA4 acetyltransferase complex yet NuA4 does not recognize methyl H3K36 nucleosomes. We found that methyl H3K36 nucleosome recognition by Rpd3S also requires the PHD domain of its Rco1 subunit. Thus, the coupled chromo and PHD domains of Rpd3S specifies recognition of the methyl H3K36 mark; demonstrating the first combinatorial domain requirement within a protein complex to read a specific histone code.

2007-05-16 | E-TABM-260 | biostudies-arrayexpress

DDM1/Lsh remodelers allow methylation of DNA wrapped in nucleosomes

Project description:Eukaryotic DNA is wrapped around histone octamers to form nucleosomes, which are separated by linker DNA bound by histone H1. In many species, the DNA exhibits methylation of CG dinucleotides, which is epigenetically inherited via a semiconservative mechanism. How methyltransferases access DNA within nucleosomes remains mysterious. Here we show that methylation of nucleosomes requires DDM1/Lsh nucleosome remodelers in Arabidopsis thaliana and mouse. We also show that removal of histone H1, which partially restores methylation in ddm1 mutants, does so primarily in the linker DNA between nucleosomes. In h1ddm1 compound mutants, substantial portions of the genome exhibit dramatically periodic methylation that approaches wild-type levels in linker DNA but is virtually absent in nucleosomes. We also present evidence that de novo methylation supplements semiconservative maintenance of CG methylation across generations. Overall, our results demonstrate that nucleosomes and H1 are barriers to DNA methylation, which are overcome by DDM1/Lsh nucleosome remodelers.

2017-11-15 | GSE96994 | GEO

Dual function of H2AK119ub1 on gene regulation via modulating canonical-PRC1 and H1-dependent chromatin compaction H2AK119ub1 deferentially fine-tunes gene expression by modulating canonical-PRC1 and H1-dependent chromatin compaction

Project description:First, we applied ChIP-seq (Chromatin Immunoprecipitation) to measure the enrichment of Cbx7, Ring1B, and H3K27me3 on DNA in WT (wild-type), Ring1bI53A, and Rybp/Yaf2-DKO ESCs. The results suggest that accumulation of cPRC1 on chromatin isn’t caused by the mis-regulation of H3K27me3 in Ring1bI53A mESCs and Rybp/Yaf2-DKO impairs the accumulation of ncPRC1 on chromatin. Next, here we adopt ChIP-seq to investigate the dynamic of Ring1B and Cbx7 on DNA during Rybp/Yaf2 degradation after IAA treatment. We found that that H2AK119ub1 plays an important role in restricting the binding of cPRC1 on chromatin and thereby compromises cPRC1-mediated chromatin compaction. And then, we carried out mRNA-seq and identified differential expressed genes among WT and Ring1bI53A mESCs. Next, we applied ChIP-seq (Chromatin Immunoprecipitation) to measure the enrichment of Cbx7, Ring1B, Jarid2, PHC1, and PCGF2 on DNA in WT (wild-type), Ring1bI53A, and Bap1-KO ESCs . The results suggest that the binding of “all cPRC1” with nucleosomes is blocked by H2AK119ub1. Finally, here we performed MNase-seq in WT and H1-QKO mESCs. We found that H1-QKO lead to a stronger decondensation of H2Aub1_enriched TSSs compared with residual TSS regions. The result of ChIP-seq for H1 and ATAC-seq (Assay for Transposase Accessible Chromatin with high-throughput sequencing) of WT and Ring1BI53A, and mRNA-seq of WT and H1-QKO mESCs suggest H2AK119ub1 represses genes via promoting H1-mediated chromatin compaction.

2024-02-11 | GSE232140 | GEO

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