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  • HISTONE H3  (6)
Keywords
  • 1
    Keywords: IN-VIVO ; MAMMALIAN-CELLS ; LIVING CELLS ; EMBRYONIC STEM-CELLS ; LYSINE-9 METHYLATION ; HP1 PROTEINS ; DNA-METHYLATION ; HISTONE H3 ; CHROMATIN-REMODELING COMPLEXES ; NUCLEOSOME MODIFICATION
    Abstract: The cell establishes heritable patterns of active and silenced chromatin via interacting factors that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts. We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2 demarcate the PCH state. From the experimental data, we developed a predictive mathematical model that explains how chromatin-bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics. This "nucleation and looping" mechanism is particularly robust toward transient perturbations and stably maintains the PCH state. These features make it an attractive model for establishing functional epigenetic domains throughout the genome based on the localized immobilization of chromatin-modifying enzymes.
    Type of Publication: Journal article published
    PubMed ID: 25134515
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  • 2
    Keywords: MODEL ; GENOME ; DNA ; DYNAMICS ; METHYLATION ; GENE-REGULATION ; CHROMATIN FIBER ; HISTONE H3 ; MATRIX FORMALISM ; CHROMODOMAIN
    Abstract: Heterochromatin protein 1 (HP1) participates in establishing and maintaining heterochromatin via its histone-modification-dependent chromatin interactions. In recent papers HP1 binding to nucleosomal arrays was measured in vitro and interpreted in terms of nearest-neighbour cooperative binding. This mode of chromatin interaction could lead to the spreading of HP1 along the nucleosome chain. Here, we reanalysed previous data by representing the nucleosome chain as a 1D binding lattice and showed how the experimental HP1 binding isotherms can be explained by a simpler model without cooperative interactions between neighboring HP1 dimers. Based on these calculations and spatial models of dinucleosomes and nucleosome chains, we propose that binding stoichiometry depends on the nucleosome repeat length (NRL) rather than protein interactions between HP1 dimers. According to our calculations, more open nucleosome arrays with long DNA linkers are characterized by a larger number of binding sites in comparison to chains with a short NRL. Furthermore, we demonstrate by Monte Carlo simulations that the NRL dependent folding of the nucleosome chain can induce allosteric changes of HP1 binding sites. Thus, HP1 chromatin interactions can be modulated by the change of binding stoichiometry and the type of binding to condensed (methylated) and non-condensed (unmethylated) nucleosome arrays in the absence of direct interactions between HP1 dimers.
    Type of Publication: Journal article published
    PubMed ID: 25563825
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  • 3
    Keywords: CANCER ; CELLS ; PROTEINS ; DIFFERENTIATION ; BINDING ; RECOGNITION ; exon-intron structure ; LYSINE 9 ; GENOME-WIDE ; HISTONE H3
    Abstract: The global impact of DNA methylation on alternative splicing is largely unknown. Using a genome-wide approach in wild-type and methylation-deficient embryonic stem cells, we found that DNA methylation can either enhance or silence exon recognition and affects the splicing of more than 20% of alternative exons. These exons are characterized by distinct genetic and epigenetic signatures. Alternative splicing regulation of a subset of these exons can be explained by heterochromatin protein 1 (HP1), which silences or enhances exon recognition in a position-dependent manner. We constructed an experimental system using site-specific targeting of a methylated/unmethylated gene and demonstrate a direct causal relationship between DNA methylation and alternative splicing. HP1 regulates this gene's alternative splicing in a methylation-dependent manner by recruiting splicing factors to its methylated form. Our results demonstrate DNA methylation's significant global influence on mRNA splicing and identify a specific mechanism of splicing regulation mediated by HP1.
    Type of Publication: Journal article published
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  • 4
    Keywords: ASSOCIATION ; DNA methylation ; RNA-POLYMERASE-II ; EMBRYONIC STEM-CELLS ; ES CELLS ; SELF-RENEWAL ; CHROMATIN-REMODELING COMPLEX ; HISTONE H3 ; CHROMOSOMAL-PROTEIN ; HP1 ISOFORMS
    Abstract: BACKGROUND: Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown. RESULTS: Here we identify Heterochromatin Protein 1beta (HP1beta) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1beta is differentially localized and differentially associated with chromatin. Deletion of HP1beta, but not HP1alpha, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1beta has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1beta in ESCs. The minor fraction of HP1beta that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters. CONCLUSIONS: We demonstrate an unexpected duality in the role of HP1beta: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1beta function both depends on, and regulates, the pluripotent state.
    Type of Publication: Journal article published
    PubMed ID: 26415775
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  • 5
    Keywords: PHOSPHORYLATION ; REVERSE-TRANSCRIPTASE ; CANCER-CELLS ; MAMMALIAN TELOMERES ; CAJAL BODIES ; HETEROCHROMATIN ; TRANSCRIPTIONAL ACTIVATION ; epigenetic regulation ; HISTONE H3 ; SERINE 10
    Abstract: Non-coding RNAs can modulate histone modifications that, at the same time, affect transcript expression levels. Here, we dissect such a network in mouse embryonic stem cells (ESCs). It regulates the activity of the reverse transcriptase telomerase, which synthesizes telomeric repeats at the chromosome ends. We find that histone H3 serine 10 phosphorylation set by Aurora kinase B (AURKB) in ESCs during the S phase of the cell cycle at centromeric and (sub)telomeric loci promotes the expression of non-coding minor satellite RNA (cenRNA). Inhibition of AURKB induces silencing of cenRNA transcription and establishment of a repressive chromatin state with histone H3 lysine 9 trimethylation and heterochromatin protein 1 accumulation. This process results in a continuous shortening of telomeres. We further show that AURKB interacts with both telomerase and cenRNA and activates telomerase in trans. Thus, in mouse ESCs, telomere maintenance is regulated via expression of cenRNA in a cell-cycle-dependent manner.
    Type of Publication: Journal article published
    PubMed ID: 26051938
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  • 6
    Keywords: GENE-EXPRESSION ; CANCER-CELLS ; PERICENTRIC HETEROCHROMATIN ; EMBRYONIC STEM-CELLS ; MAMMALIAN TELOMERES ; HISTONE H3 ; ATRX ; REPEAT-CONTAINING RNA ; R-LOOPS ; DNA HYBRIDS
    Abstract: Long noncoding telomeric repeat-containing RNA (TERRA) has been implicated in telomere maintenance in a telomerase-dependent and a telomerase-independent manner during replicative senescence and cancer. TERRA's proposed activities are diverse, thus making it difficult to pinpoint the critical roles that TERRA may have. We propose that TERRA orchestrates different activities at chromosome ends in a manner that depends on the state of the telomere.
    Type of Publication: Journal article published
    PubMed ID: 26581519
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