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Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line

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Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Confining euchromatin/heterochromatin territory: jumonji crosses the line Hisashi Tamaru1 Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of Sciences, 1030 Vienna, Austria Heterochromatin is typically highly condensed, gene-poor, Richards and Elgin 2002; Suzuki and Bird 2008). Pericen- and transcriptionally silent, whereas euchromatin is less tromeric and telomeric regions that contain a high density condensed, gene-rich, and more accessible to transcription. of repetitive DNA elements, such as clusters of satellite Besides acting as a graveyard for selfish mobile DNA re- sequences and transposons, are the main targets for hetero- peats, heterochromatin contributes to important biological chromatin formation (Martens et al. 2005; Schueler and functions, such as chromosome segregation during cell Sullivan 2006; Blasco 2007; Slotkin and Martienssen 2007; division. Multiple features of heterochromatin—including Schoeftner and Blasco 2009). Centromeric heterochromatin the presence or absence of specific histone modifications, is required for correct chromosome segregation (Peters DNA methylation, and small RNAs—have been implicated et al. 2001; Lippman and Martienssen 2004; Kanellopoulou in distinguishing heterochromatin from euchromatin in et al. 2005; Pidoux and Allshire 2005; Folco et al. 2008). A de- various organisms. Cells malfunction if the genome fails fining feature of heterochromatin is that it self-perpetuates to restrict repressive chromatin marks within heterochro- its transcriptionally repressed state and highly condensed matin domains. How euchromatin and heterochromatin structure on chromosomes in a region-specific manner territories are confined remains poorly understood. Re- throughout the cell cycle over generations. cent studies from the fission yeast Schizosaccharomyces Two pathways for initiating heterochromatin forma- pombe, the flowering plant Arabidopsis thaliana, and the tion are known. The first is an RNAi-based self-enforcing filamentous fungus Neurospora crassa have revealed a new loop mechanism that targets H3K9me by histone meth- role for Jumonji C (JmjC) domain-containing proteins in yltransferases (HMTs) to repetitive DNA elements using protecting euchromatin from heterochromatin marks. siRNAs that are complementary to the target (Hall et al. 2002; Volpe et al. 2002; Verdel et al. 2004). In Schizosac- The nucleosome is the basic unit of a eukaryotic chro- charomyces pombe, the RITS (RNA-induced transcrip- mosome, consisting of 146 base pairs (bp) of DNA coiled tional silencing) complex, composed of a chromodomain around a core consisting of a histone octamer (Luger et al. protein (Chp1), Argonaute (Ago1), and Tas3, together with 1997). Chromosomes have two structurally and function- siRNAs, cooperates with RNA-dependent RNA polymer- ally distinguishable territories: euchromatin and hetero- ase (Rdp1) and other factors such as Dicer (Dcr1) to process chromatin. Heterochromatin is highly condensed, gene- repeat transcripts into siRNAs (Motamedi et al. 2004; poor, and transcriptionally silent, whereas euchromatin Noma et al. 2004; Verdel et al. 2004; Sugiyama et al. 2005). is less condensed, gene-rich, and more easily transcribed RNAi-mediated heterochromatin targeting is found in (Huisinga et al. 2006). Nucleosome modifications distin- many eukaryotic systems, including fission yeast, animals, guish heterochromatin from euchromatin. Euchromatin and plants. In addition, ties have been found between is typically enriched in acetylated histones H3 and H4 RNAi and DNA methylation. In mammals and plants, and H3K4 methylation (H3K4me) (Grunstein 1998; Litt dsRNAs can direct DNA methylation of its homologous et al. 2001; Noma et al. 2001), whereas heterochromatin sequences (Wassenegger et al. 1994; Wassenegger 2000; is characterized by hypoacetylation of histones, H3K9me Morris et al. 2004; Bayne and Allshire 2005; Matzke and (Tschiersch et al. 1994; Rea et al. 2000; Jenuwein and Allis Birchler 2005; Law and Jacobsen 2010). The second path- 2001; Nakayam et al. 2001; Schotta et al. 2002), associ- way is DNA-based and relies on sequence-specific DNA- ation of heterochromatin protein-1 (HP1) (Eissenberg binding proteins to deliver HMT activity to specific et al. 1990; Bannister et al. 2001; Lachner et al. 2001; genomic locations. For example, the transcription factors Lachner and Jenuwein 2002), and DNA cytosine methyl- Atf1 and Pcr1 cooperate with Clr3 histone deacetylase ation (5mC) in organisms showing this modification (HDAC) to nucleate H3K9me at heterochromatic loci of (Keshet et al. 1986; Buschhausen et al. 1987; Hennig 1999; S. pombe (Jia et al. 2004a; Yamada et al. 2005). The RNAi-directed targeting of H3K9me to a specific [Keywords: JmjC; 5mC; H3K9me; euchromatin/heterochromatin; heterochromatin nucleation site triggers a self-reinforcing transcription] cycle of chain reactions between nucleosome modifica- 1Correspondence. E-MAIL [email protected]; FAX 43-1-790449001. tions and binding proteins. In most eukaryotes, the chro- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1941010. modomain of HP1 binds to the H3K9me mark and recruits GENES & DEVELOPMENT 24:1465–1478 Ó 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org 1465 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Tamaru additional nucleosome-modifying enzymes, leading to the post-transcriptional gene silencing (PTGS), called quelling propagation of HP1-containing heterochromatin (Grewal (Cogoni et al. 1996; Cogoni and Macino 1999a,b; Cogoni and Jia 2007). Importantly, heterochromatin assembled at 2001), and transcriptional gene silencing through DNA a specific nucleation site can spread along the chromatin methylation are independent genome defense systems. fiber through direct or indirect interactions between This review highlights a recent Genes & Development nucleosome-modifying enzymes and structural hetero- paper from the Selker laboratory (Honda et al. 2010) chromatin proteins such as HP1 (Eissenberg and Reuter implicating a Jumonji C (JmjC) domain protein, DNA 2009). The spread of heterochromatin formation fre- methylation modulator-1 (DMM-1), in confining euchro- quently causes position-effect variegation (PEV), the matin/heterochromatin domains in N. crassa. Compari- metastable and heritable silencing of a euchromatic gene sons are made with two other JmjC domain proteins, Epe1 (Baker 1968; Eissenberg 1989; Henikoff 1990; Schotta et al. and INCREASE IN BONSAI METHYLATION1 (IBM1), 2003; Talbert and Henikoff 2006), which could have from S. pombe and Arabidopsis thaliana, respectively. a detrimental effect on normal cell functions. Therefore, cells have evolved mechanisms to limit inappropriate infiltration of heterochromatin into euchromatin. Specific The DMM-1 JmjC domain protein in the filamentous DNA barrier (or insulator) elements that function to fungus N. crassa protect genes against silencing effects of adjacent hetero- RIP generates signals for heterochromatin formation chromatin have been identified in several organisms. For in N. crassa instance, the transcription factor USF1 binds within the insulator element at the 59 end of the chicken b-globin Heterochromatin formation in N. crassa involves efficient locus flanked by condensed chromatin, and recruits eu- targeting of H3K9me3, HP1, and 5mC to chromosome chromatin-promoting enzymatic activities such as his- regions containing RIP-mutated (RIP’d) DNA, including tone acetyltransferases (HATs), H3K4, and H4R3 HMTs, centromeres, telomeres, and transposon relics (Selker thereby counteracting the propagation of heterochroma- et al. 2003; Lewis et al. 2009). RIP detects duplicated tin (Gaszner and Felsenfeld 2006; S Huang et al. 2007). In DNA fragments—regardless of their transcriptional state S. pombe, DNA boundary elements flank heterochroma- or foreign or native source—in a pairwise manner, and tin domains at the mating type locus and centromeres mutates them with numerous G:C to A:T transition (Noma et al. 2001, 2006; Thon et al. 2002) and block the mutations in the sexual phase of the life cycle (Cambareri spreading of heterochromatin and associated factors, in- et al. 1989; Selker 1990). RIP preferentially mutates CpA to cluding the RITS complex and the HDAC complex SHREC TpA dinucleotides (Singer et al. 1995). As a consequence, containing Clr3 (Jia et al. 2004b; Noma et al. 2004; Yamada RIP’d DNA sequences are both TpA- and A:T-rich. Hence, et al. 2005; Sugiyama et al. 2007). In Drosophila, which analyses of the ‘‘RIP product index’’ (TpA/ApT) and the does not show fixed DNA barriers, the boundary between ‘‘RIP substrate index’’ (CpA +TpG/ApC + GpT) can identify heterochromatin and euchromatin is thought to be de- sequences that have undergone RIP in the Neurospora termined by the local balance between the strength of genome (Margolin et al. 1998; Selker et al. 2003). Consis- activities that promote either heterochromatin or euchro- tent with the hypothesis that RIP serves to control selfish matin (Sun et al. 2004; Gaszner and Felsenfeld 2006). DNA, such as mobile elements, analyses of the sequences The filamentous fungus Neurospora crassa shows all of of the N. crassa genome revealed a complete absence of the key features of heterochromatin in higher eukaryotes, intact mobile elements (Galagan et al. 2003; Galagan
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