Nielsen, S.J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561-565

Wellcome/CRC Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QR, UK.
Nature (Impact Factor: 41.46). 09/2001; 412(6846):561-5. DOI: 10.1038/35087620
Source: PubMed


In eukaryotic cells the histone methylase SUV39H1 and the methyl-lysine binding protein HP1 functionally interact to repress transcription at heterochromatic sites. Lysine 9 of histone H3 is methylated by SUV39H1 (ref. 2), creating a binding site for the chromo domain of HP1 (refs 3, 4). Here we show that SUV39H1 and HP1 are both involved in the repressive functions of the retinoblastoma (Rb) protein. Rb associates with SUV39H1 and HP1 in vivo by means of its pocket domain. SUV39H1 cooperates with Rb to repress the cyclin E promoter, and in fibroblasts that are disrupted for SUV39, the activity of the cyclin E and cyclin A2 genes are specifically elevated. Chromatin immunoprecipitations show that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter. These results indicate that the SUV39H1-HP1 complex is not only involved in heterochromatic silencing but also has a role in repression of euchromatic genes by Rb and perhaps other co-repressor proteins.

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    • "Since Suv39H1 is one of the proteins that show dynamic interaction with heterochromatin regions and some inactive promoters of silenced genes (25,41–43), we next assessed whether phosphorylation of Suv39H1 affects its binding capacity to heterochromatin regions using a ChIP assay. Under asynchronous growth conditions, phospho-mimic Suv39H1 (Suv39H1-S391E) had decreased binding affinity to heterochromatin regions relative to wild-type or phospho-defective Suv39H1 (S391A) proteins in both transiently and stably expressing cells (Figure 3A and B, Supplementary Figure S7), suggesting that phospho-mimic Suv39H1 protein preferentially dissociates from heterochromatin regions. "
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    ABSTRACT: Although several studies have suggested that the functions of heterochromatin regulators may be regulated by post-translational modifications during cell cycle progression, regulation of the histone methyltransferase Suv39H1 is not fully understood. Here, we demonstrate a direct link between Suv39H1 phosphorylation and cell cycle progression. We show that CDK2 phosphorylates Suv39H1 at Ser391 and these phosphorylation levels oscillate during the cell cycle, peaking at S phase and maintained during S-G2-M phase. The CDK2-mediated phosphorylation of Suv39H1 at Ser391 results in preferential dissociation from chromatin. Furthermore, phosphorylation-mediated dissociation of Suv39H1 from chromatin causes an enhanced occupancy of JMJD2A histone demethylase on heterochromatin and alterations in inactive histone marks. Overexpression of phospho-mimic Suv39H1 induces early replication of heterochromatin, suggesting the importance of Suv39H1 phosphorylation in the replication of heterochromatin. Moreover, overexpression of phospho-defective Suv39H1 caused altered replication timing of heterochromatin and increases sensitivity to replication stress. Collectively, our data suggest that phosphorylation-mediated modulation of Suv39H1-chromatin association may be an initial step in heterochromatin replication.
    Nucleic Acids Research 04/2014; 42(10). DOI:10.1093/nar/gku263 · 9.11 Impact Factor
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    • "However, they can do it both directly and indirectly, and in a very broad scale, recruiting co-repressors/activators to specific transcription factors. Recent studies propose Rb proteins to bind co-repressors: histones deacetylases (HDAC1, HDAC2) (56–58), histone de-methylases (RBP2) (59), DNA methyl transferases (DNMT1) (60), helicases (Brg1, Brm) (61, 62), histone methyl transferases (Suv39h1, RIZ, suv4-20h1/h2) (63–65), and histone binding proteins, like HP1, regulating chromatin structure and transcription (63, 66). In this context, the interaction with E2F directs pocket proteins to DNA domains leads to transcriptional repression. "
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    ABSTRACT: The Rb1 gene was the first bona fide tumor suppressor identified and cloned more than 25 years ago. Since then, a plethora of studies have revealed the functions of pRb and the existence of a sophisticated and strictly regulated pathway that modulates such functional roles. An emerging paradox affecting Rb1 in cancer connects the relatively low number of mutations affecting Rb1 gene in specific human tumors, compared with the widely functional inactivation of pRb in most, if not in all, human cancers. The existence of a retinoblastoma family of proteins pRb, p107, and p130 and their potential unique and overlapping functions as master regulators of cell cycle progression and transcriptional modulation by similar processes, may provide potential clues to explain such conundrum. Here, we will review the development of different genetically engineered mouse models, in particular those affecting stratified epithelia, and how they have offered new avenues to understand the roles of the Rb family members and their targets in the context of tumor development and progression.
    Frontiers in Oncology 12/2013; 3:307. DOI:10.3389/fonc.2013.00307
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    • "Global gene expression analysis comparing rag2-hKRASG12D/rag2-hSUV39H1 with rag2-hKRASG12D/rag2-mCherry 7dpf larvae revealed that cyclin B1 is downregulated in the SUV39H1-overexpressing tumors, which was confirmed by qPCR. SUV39H1 is already known to silence cyclins E and A [30]. Silencing of cyclin B1 may explain how SUV39H1 promotes senescence and growth arrest. "
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    ABSTRACT: Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRAS(G12D)-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRAS(G12D) overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.
    PLoS ONE 05/2013; 8(5):e64969. DOI:10.1371/journal.pone.0064969 · 3.23 Impact Factor
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