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      Role of Polycomb Proteins in Regulating HSV-1 Latency

      review-article
      , , , , *
      Viruses
      MDPI
      HSV, herpes, PRC, Polycomb, heterochromatin, latency, reactivation

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          Abstract

          Herpes simplex virus (HSV) establishes a latent infection within sensory neurons of humans. Latency is characterized by the transcriptional repression of lytic genes by the condensation of lytic gene regions into heterochromatin. Recent data suggest that facultative heterochromatin predominates, and that cellular Polycomb proteins are involved in the establishment and maintenance of transcriptional repression during latency. This review summarizes these data and discusses the implication of viral and cellular factors in regulating heterochromatin composition.

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          Most cited references63

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          Regulation of LSD1 histone demethylase activity by its associated factors.

          LSD1 is a recently identified human lysine (K)-specific histone demethylase. LSD1 is associated with HDAC1/2; CoREST, a SANT domain-containing corepressor; and BHC80, a PHD domain-containing protein, among others. We show that CoREST endows LSD1 with the ability to demethylate nucleosomal substrates and that it protects LSD1 from proteasomal degradation in vivo. We find hyperacetylated nucleosomes less susceptible to CoREST/LSD1-mediated demethylation, suggesting that hypoacetylated nucleosomes may be the preferred physiological substrates. This raises the possibility that histone deacetylases and LSD1 may collaborate to generate a repressive chromatin environment. Consistent with this model, TSA treatment results in derepression of LSD1 target genes. While CoREST positively regulates LSD1 function, BHC80 inhibits CoREST/LSD1-mediated demethylation in vitro and may therefore confer negative regulation. Taken together, these findings suggest that LSD1-mediated histone demethylation is regulated dynamically in vivo. This is expected to have profound effects on gene expression under both physiological and pathological conditions.
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            Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases.

            Covalent modifications of histones, such as acetylation and methylation, play important roles in the regulation of gene expression. Histone lysine methylation has been implicated in both gene activation and repression, depending on the specific lysine (K) residue that becomes methylated and the state of methylation (mono-, di-, or trimethylation). Methylation on K4, K9, and K36 of histone H3 has been shown to be reversible and can be removed by site-specific demethylases. However, the enzymes that antagonize methylation on K27 of histone H3 (H3K27), an epigenetic mark important for embryonic stem cell maintenance, Polycomb-mediated gene silencing, and X chromosome inactivation have been elusive. Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), as well as the related JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro. Further, the demethylase activity of UTX requires a catalytically active JmjC domain. Finally, overexpression of UTX and JMJD3 leads to reduced di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may function as H3K27 demethylases in vivo. The identification of UTX and JMJD3 as H3K27-specific demethylases provides direct evidence to indicate that similar to methylation on K4, K9, and K36 of histone H3, methylation on H3K27 is also reversible and can be dynamically regulated by site-specific histone methyltransferases and demethylases.
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              Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains.

              On the histone H3 tail, Lys 9 and Lys 27 are both methylation sites associated with epigenetic repression, and reside within a highly related sequence motif ARKS. Here we show that the chromodomain proteins Polycomb (Pc) and HP1 (heterochromatin protein 1) are highly discriminatory for binding to these sites in vivo and in vitro. In Drosophila S2 cells, and on polytene chromosomes, methyl-Lys 27 and Pc are both excluded from areas that are enriched in methyl-Lys 9 and HP1. Swapping of the chromodomain regions of Pc and HP1 is sufficient for switching the nuclear localization patterns of these factors, indicating a role for their chromodomains in both target site binding and discrimination. To better understand the molecular basis for the selection of methyl-lysine binding sites, we solved the 1.8 A structure of the Pc chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared it with our previously determined structure of the HP1 chromodomain in complex with a H3 peptide bearing trimethyl-Lys 9. The Pc chromodomain distinguishes its methylation target on the H3 tail via an extended recognition groove that binds five additional residues preceding the ARKS motif.
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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                15 July 2013
                July 2013
                : 5
                : 7
                : 1740-1757
                Affiliations
                Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL 32610, USA; E-Mails: levis501ufl.edu (Z.W.); dhummaa@ 123456ufl.edu (A.D.); hmesser@ 123456ufl.edu (H.M.); dphelan@ 123456ufl.edu (D.P.)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: dbloom@ 123456ufl.edu ; Tel.: +1-352-273-9524; Fax: +1-352-273-8905.
                Article
                viruses-05-01740
                10.3390/v5071740
                3738959
                23860385
                08760fcb-0b85-4a37-b986-1d647520b5a0
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 29 May 2013
                : 04 July 2013
                : 04 July 2013
                Categories
                Review

                Microbiology & Virology
                hsv,herpes,prc,polycomb,heterochromatin,latency,reactivation
                Microbiology & Virology
                hsv, herpes, prc, polycomb, heterochromatin, latency, reactivation

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