Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3

Jacobs, Steven; Taverna, Sean D.; Zhang, Yinong; Briggs, Scott; Li, Jinmei; Eissenberg, Joel C.; Allis, C. David; Khorasanizadeh, Sepideh

doi:10.1093/emboj/20.18.5232

Cited by 372 publications

(328 citation statements)

References 51 publications

(80 reference statements)

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“…Methylation at histone H3-K9 that is specifically catalyzed by Suv39h has recently been shown to be a marker of heterochromatin, 19,25,26,38 and histone H3-K9 methylation contributes to establishing and maintaining heterochromatin by providing a binding site for heterochromatin protein 1 (HP 1). 39,40 Strahl and Allis have proposed that distinct histone modifications on 1 or more tails act sequentially or in combination to form a ''histone code'' that is read by other proteins to bring about distinct downstream events. 41 According to our ChIP 5 results, this view of the ''histone code'' might apply to the regulation of MUC2.…”

Section: Discussionmentioning

confidence: 99%

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Yamada

Hamada

Goto

et al. 2006

Intl Journal of Cancer

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Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5 0 flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Yamada

Hamada

Goto

et al. 2006

Intl Journal of Cancer

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“…mutation V26M (Fig. 5D), which abolishes H3K9me2/3 binding (Jacobs et al 2001). Thus, HP1a requires an intact CSD dimer interface for binding to PIWI.…”

Section: Hp1a Binds To a Pxvxv Motif In The N-terminal Domain Of Piwimentioning

confidence: 99%

Drosophila PIWI associates with chromatin and interacts directly with HP1a

Brower-Toland¹,

Findley²,

Jiang³

et al. 2007

Genes Dev.

313

292

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The interface between cellular systems involving small noncoding RNAs and epigenetic change remains largely unexplored in metazoans. RNA-induced silencing systems have the potential to target particular regions of the genome for epigenetic change by locating specific sequences and recruiting chromatin modifiers. Noting that several genes encoding RNA silencing components have been implicated in epigenetic regulation in Drosophila, we sought a direct link between the RNA silencing system and heterochromatin components. Here we show that PIWI, an ARGONAUTE/PIWI protein family member that binds to Piwi-interacting RNAs (piRNAs), strongly and specifically interacts with heterochromatin protein 1a (HP1a), a central player in heterochromatic gene silencing. The HP1a dimer binds a PxVxL-type motif in the N-terminal domain of PIWI. This motif is required in fruit flies for normal silencing of transgenes embedded in heterochromatin. We also demonstrate that PIWI, like HP1a, is itself a chromatin-associated protein whose distribution in polytene chromosomes overlaps with HP1a and appears to be RNA dependent. These findings implicate a direct interaction between the PIWI-mediated small RNA mechanism and heterochromatin-forming pathways in determining the epigenetic state of the fly genome.[Keywords: PIWI; ARGONAUTE; HP1; heterochromatin; epigenetic; RNAi] Supplemental material is available at http://www.genesdev.org. . In TGS, small RNAs are incorporated into specialized effector complexes able to regulate chromatin modification, resulting in reduced access for the transcriptional machinery to chromatin. The TGS system that contributes to initiation and maintenance of heterochromatin formation in Schizosaccharomyces pombe is particularly well characterized (Verdel and Moazed 2005;Grewal and Jia 2007). In S. pombe, the RNA silencing system targets histone 3 Lys 9 (H3K9) methylation and recruits HP1 homolog Swi6 to the MAT locus and to repetitive elements in pericentric heterochromatin, setting up a heterochromatin spreading/maintenance loop that is dependent on the interaction of Swi6 with the Clr4 histone methyltransferase (HMT) (Grewal and Jia 2007). In plants, a specialized small RNA pathway utilizes heterochromatic RNAs to direct DNA methylation and presumably other chromatin modifications to effect silencing of target loci (for review, see Vaucheret 2007). In Caenorhabditis elegans, a single episode of RNA interference (RNAi) exposure can induce silencing inherited over many generations; mutations that abolish inheritance are all involved in chromatin structure, suggesting a chromatin-based mechanism (Vastenhouw et al. 2006). While the work in fission yeast and plants provides a possible paradigm for RNAi-dependent TGS in metazoans, a specialized TGS effector complex has not yet been characterized in an animal.

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“…This may be explained by the fact that acetylation of Lys 9 residues prevents methylation by the SUV39H1 methyltransferase (Rea et al, 2000, Nakayama et al, 2001. Given the strong specificity of the HP1/Swi6 chromodomain for Lys 9 methylated H3 (Bannister et al, 2001;Jacobs et al, 2001;Nakayama et al, 2001), HP1 association to heterochromatin containing Lys 9 acetylated H3 may be defective. Our data show that acetylation-dependent defective accumulation of HP1 onto heterochromatin occurs not only after several day exposure to TSA, as shown by Taddei et al (2001), but also when histones are maintained hyperacetylated specifically during prophase.…”

Section: Chromosome Structure Is Profoundly Altered When Histones Arementioning

confidence: 99%

Histone Hyperacetylation in Mitosis Prevents Sister Chromatid Separation and Produces Chromosome Segregation Defects

Cimini

Mattiuzzo

Torosantucci

et al. 2003

MBoC

166

151

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Posttranslational modifications of core histones contribute to driving changes in chromatin conformation and compaction. Herein, we investigated the role of histone deacetylation on the mitotic process by inhibiting histone deacetylases shortly before mitosis in human primary fibroblasts. Cells entering mitosis with hyperacetylated histones displayed altered chromatin conformation associated with decreased reactivity to the anti-Ser 10 phospho H3 antibody, increased recruitment of protein phosphatase 1-δ on mitotic chromosomes, and depletion of heterochromatin protein 1 from the centromeric heterochromatin. Inhibition of histone deacetylation before mitosis produced defective chromosome condensation and impaired mitotic progression in living cells, suggesting that improper chromosome condensation may induce mitotic checkpoint activation. In situ hybridization analysis on anaphase cells demonstrated the presence of chromatin bridges, which were caused by persisting cohesion along sister chromatid arms after centromere separation. Thus, the presence of hyperacetylated chromatin during mitosis impairs proper chromosome condensation during the pre-anaphase stages, resulting in poor sister chromatid resolution. Lagging chromosomes consisting of single or paired sisters were also induced by the presence of hyperacetylated histones, indicating that the less constrained centromeric organization associated with heterochromatin protein 1 depletion may promote the attachment of kinetochores to microtubules coming from both poles

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Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3

Cited by 372 publications

References 51 publications

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Drosophila PIWI associates with chromatin and interacts directly with HP1a

Histone Hyperacetylation in Mitosis Prevents Sister Chromatid Separation and Produces Chromosome Segregation Defects

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