Independence of Repressive Histone Marks and Chromatin Compaction during Senescent Heterochromatic Layer Formation

Chandra, Tamir; Kirschner, Kristina; Thuret, Jean‐Yves; Pope, Benjamin D.; Ryba, Tyrone; Newman, Scott; Ahmed, Kashif; Samarajiwa, Shamith A.; Salama, Rafik; Carroll, Thomas; Stark, Rory; Janky, Rekin’s; Narita, Masako; Xue, Lixiang; Chicas, Agustin; Nuñez, Sabrina; Janknecht, Ralf; Hayashi‐Takanaka, Yoko; Wilson, Michael D.; Marshall, Aileen; Odom, Duncan T.; Babu, M. Madan; Bazett-Jones, David P.; Tavaré, Simon; Edwards, Paul A.W.; Lowe, Scott W.; Kimurâ, Hiroshi; Gilbert, David M.; Narita, Masashi

doi:10.1016/j.molcel.2012.06.010

Cited by 266 publications

(324 citation statements)

References 49 publications

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“…For example, the repressive mark H3K27me3 has been reported to associate with early to mid replication and with early and mid origins (Chandra et al, 2012;Julienne et al, 2013;Picard et al, 2014), as well as with late replication (Thurman et al, 2007). In our data, peaks of H3K27me3 appear to follow two different patterns.…”

Section: Replication Timing In Relation To Chromatin Packagingmentioning

confidence: 42%

Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips

Wear

Song²,

Zynda³

et al. 2017

Plant Cell

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All plants and animals must replicate their DNA, using a regulated process to ensure that their genomes are completely and accurately replicated. DNA replication timing programs have been extensively studied in yeast and animal systems, but much less is known about the replication programs of plants. We report a novel adaptation of the "Repli-seq" assay for use in intact root tips of maize (Zea mays) that includes several different cell lineages and present whole-genome replication timing profiles from cells in early, mid, and late S phase of the mitotic cell cycle. Maize root tips have a complex replication timing program, including regions of distinct early, mid, and late S replication that each constitute between 20 and 24% of the genome, as well as other loci corresponding to ;32% of the genome that exhibit replication activity in two different time windows. Analyses of genomic, transcriptional, and chromatin features of the euchromatic portion of the maize genome provide evidence for a gradient of early replicating, open chromatin that transitions gradually to less open and less transcriptionally active chromatin replicating in mid S phase. Our genomic level analysis also demonstrated that the centromere core replicates in mid S, before heavily compacted classical heterochromatin, including pericentromeres and knobs, which replicate during late S phase.

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Section: Replication Timing In Relation To Chromatin Packagingmentioning

confidence: 42%

Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips

Wear

Song²,

Zynda³

et al. 2017

Plant Cell

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“…However there are mainly two lines that stand out from the block of active marks in the hierarchical clustering dendrogram in Figure 1. One of these lines corresponds to the polycomb (Pc) associated repressive chromatin marks H3K27me3 characteristics of the so-called facultative heterochromatin (Barski et al 2007;Chandra et al 2012). This is the only mark that anti-correlates with most of the active marks except H4K20me1.…”

Section: Combinatorial Analysis Of Chromatin Marks At Human Gene Prommentioning

confidence: 99%

Epigenetic regulation of the human genome: coherence between promoter activity and large-scale chromatin environment

Julienne

Zoufir

Audit

et al. 2013

Frontiers in Life Science

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Increasing knowledge of chromatin structure in various cell types raises the challenge of deciphering the contribution of epigenetic modifications to the regulation of nuclear functions in mammals. In a recent study, we have analysed the genomewide distributions of thirteen epigenetic marks in the human cell line K562 at 100 kb resolution of Mean Replication Timing (MRT) data. Using classical clustering techniques, we have shown that the combinatorial complexity of these epigenetic data can be reduced to four predominant chromatin states that replicate at different periods of the S-phase. C1 is an early replicating transcriptionally active euchromatin state, C2 a mid-S repressive type of chromatin associated with Polycomb complexes, C3 a silent chromatin with lack of chromatin marks that replicates later than C2 but before C4, a HP1-associated heterochromatin state that replicates at the end of S-phase. These four chromatin states display remarkable similarities with those recently reported in fly, worm and plants at higher ∼ 1 kb resolution of gene expression data. Here, we extend our integrative analysis of epigenetic data in the K562 human cell line to this smaller scale by focusing on gene promoters (±3 kb around transcription start sites). We show that these promoters can similarly be classified into four main chromatin states: P1 regroups all the marks of transcriptionally active chromatin and corresponds to CpG rich promoters of highly expressed genes; P2 is notably associated with the histone modification H3K27me3 that is the mark of a polycomb repressed chromatin state; P3 corresponds to promoters that are not enriched for any available marks as the signature of a 'null' or 'black' silent heterochromatin state and P4 characterizes the few gene promoters that contain only the constitutive heterochromatin histone modification H3K9me3. When investigating the coherence between promoter activity (P1, P2, P3 or P4) and the large-scale chromatin environment (C1, C2, C3 or C4), we find that the higher the gene density in a considered 100 kb-window, the higher (resp. the lower) the probability of a P1 active promoter (resp. silent P2, P3 and P4 promoters) to be surrounded by an open euchromatin C1 (resp. facultative C2, black C3 or HP1-associated C4 heterochromatin) environment. From large to small scales, it is mainly C4 and to a lesser extent C3 heterochromatin environments both corresponding to gene poor regions, that strongly conditions promoters to belong to the inactive P3 and P4 classes. If C1 (resp. C2) environment surrounds a majority of corresponding active P1 (resp. P2) promoters, it also contains a non-negligible proportion of inactive P2 and P3 (resp. active P1 and inactive P3) promoters. When further investigating the large-scale organization of human genes with respect to 'master' replication origins that were shown to border megabase-sized U-shaped MRT domains, we reveal some significant enrichment of highly expressed P1 genes in a closed neighbourhood of these early initiation zones consistently...

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“…1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF).…”

mentioning

confidence: 99%

“…7,[9][10][11] Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. [12][13][14] Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senescence regulator, which is typically activated during senescence and enforces the expression of other senescence-inducing proteins.…”

mentioning

confidence: 99%

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...

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Independence of Repressive Histone Marks and Chromatin Compaction during Senescent Heterochromatic Layer Formation

Cited by 266 publications

References 49 publications

Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips

Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips

Epigenetic regulation of the human genome: coherence between promoter activity and large-scale chromatin environment

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

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