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Targeting Heterochromatin Formation to Transposable Elements in Drosophila: Potential Roles of the Pirna System

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Targeting Heterochromatin Formation to Transposable Elements in Drosophila: Potential Roles of the Pirna System Washington University in St. Louis Washington University Open Scholarship Biology Faculty Publications & Presentations Biology 6-2013 Targeting heterochromatin formation to transposable elements in Drosophila: potential roles of the piRNA system Monica F. Sentmanat Washington University in St. Louis, [email protected] SH Wang Washington University in St. Louis Sarah C.R. Elgin Washington University in St. Louis, [email protected] Follow this and additional works at: https://openscholarship.wustl.edu/bio_facpubs Part of the Biology Commons Recommended Citation Sentmanat, Monica F.; Wang, SH; and Elgin, Sarah C.R., "Targeting heterochromatin formation to transposable elements in Drosophila: potential roles of the piRNA system" (2013). Biology Faculty Publications & Presentations. 171. https://openscholarship.wustl.edu/bio_facpubs/171 This Article is brought to you for free and open access by the Biology at Washington University Open Scholarship. It has been accepted for inclusion in Biology Faculty Publications & Presentations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. ISSN 00062979, Biochemistry (Moscow), 2013, Vol. 78, No. 6, pp. 562571. © Pleiades Publishing, Ltd., 2013. Published in Russian in Biokhimiya, 2013, Vol. 78, No. 6, pp. 735746. REVIEW Targeting Heterochromatin Formation to Transposable Elements in Drosophila: Potential Roles of the piRNA System M. Sentmanat, S. H. Wang, and S. C. R. Elgin* Department of Biology, Washington University, Campus Box 1137, One Brookings Drive, St. Louis, MO 631304899, USA; fax: (314) 9354432; Email: [email protected] Received January 21, 2013 Revision received February 22, 2013 Abstract—Successful heterochromatin formation is critical for genome stability in eukaryotes, both to maintain structures needed for mitosis and meiosis and to silence potentially harmful transposable elements. Conversely, inappropriate hete rochromatin assembly can lead to inappropriate silencing and other deleterious effects. Hence targeting heterochromatin assembly to appropriate regions of the genome is of utmost importance. Here we focus on heterochromatin assembly in Drosophila melanogaster, the model organism in which variegation, or celltocell variable gene expression resulting from heterochromatin formation, was first described. In particular, we review the potential role of transposable elements as genet ic determinants of the chromatin state and examine how small RNA pathways may participate in the process of targeted het erochromatin formation. DOI: 10.1134/S0006297913060023 Key words: heterochromatin, genome stability, transposable elements Heterochromatin is classically defined as densely cells but not others [2]. Along a chromosome, constitutive packaged, peripherally localized chromatin within the heterochromatin is usually found at pericentric repeats cell nucleus. The repetitious sequence content of eukary and telomeres, while facultative heterochromatin can be otic genomes was initially recognized by quantitative interspersed along the chromosome arms. DNA reassociation analysis (generating C0t curves) using In the fruit fly, Drosophila melanogaster, heterochro principles pioneered by Roy Britten and colleagues [1]. matin becomes visible during nuclear cycles 1114 of These studies, coupled with in situ hybridization tech embryogenesis (34 h), reflecting a pattern of posttrans niques, revealed the abundance and arrangement of lational histone modifications that persists throughout repetitive DNA, and ultimately led to the understanding development [36]. Most constitutive heterochromatic that heterochromatin is enriched in satellite and trans sites are enriched for histone H3 lysine 9 di and tri posable element sequences of varying copy number. methylation (H3K9me2/3), the chromodomain protein Although understanding genome organization within the HP1a, and the histone methyltransferase (HMT) more complex, generich euchromatic compartment SU(VAR)39, whose catalytic SET domain delivers the took precedence for many years, heterochromatin has H3K9me2/3 mark. In plants, mammals, and some other recently received more attention with the development of organisms constitutive heterochromatin is also associated improved sequencing technologies and bioinformatics with DNA methylation at CpG or CpNpG sequences. strategies. These tools have enabled improved assemblies Two additional SET domain proteins have been identified and significant annotation of the repetitious sequences in Drosophila, dSETDB1 (encoded by egg) and G9a; both present in heterochromatin in many instances. are also H3K9 histone methyltransferases, although In a complex organism, those DNA sequences pack SU(VAR)39 and dSETDB1 appear to have the dominant aged as heterochromatin in all cell types are referred to as roles [7]. “constitutive heterochromatin”, while DNA packaged as Errors in establishing patterns of constitutive hete “facultative heterochromatin” (important for develop rochromatin can lead to genome instability through a mentally controlled genes) occurs in this form in some number of mechanisms. A few examples will illustrate the possibilities. Functional studies that deplete SU(VAR)3 * To whom correspondence should be addressed. 9 homologues in mammals or in yeast have shown that the 562 TARGETING HETEROCHROMATIN FORMATION TO TRANSPOSABLE ELEMENTS IN Drosophila 563 protein is important for kinetochore assembly and chro nucleosomefree region) at the transcription start site mosome segregation [8, 9], while a loss of HP1a in [17]. Biochemical analysis across the inverted breakpoint Drosophila results in telomere fusions [10]. Another form of one strain from the wm collection, wm4, shows variable of instability resulting from the loss of heterochromatin enrichment of heterochromatin proteins along a 30 kb (HP1a in particular) in the female germline is the activa stretch or more, suggesting some sequence determinants tion of transposable elements [11], which can lead to might be more susceptible than others to ectopic hete double strand breaks as well as the mutagenizing effects of rochromatin assembly [6, 18]. Together, these observa TE insertions within proteincoding DNA. In contrast, tions suggest that heterochromatin assembly can spread gainoffunction mutations in Su(var)39 cause hete in cis, provided a permissible sequence context and suffi rochromatin expansion, leading to female sterility in cient transacting molecules. These properties have made Drosophila [12]. PEV a widely used model with which to dissect the cis The appropriate targeting of facultative heterochro and transacting factors responsible for heterochromatin matin is equally important, as this system plays a key role assembly. in cell identity. Wellstudied examples of this phenome Localized distribution of heterochromatin in the non include Xinactivation in mammals and the hete genome implies an underlying sequence determinant for rochromatin formation observed during bird erythro its targeted formation. The immediate question following poiesis, when the majority of the genome is silenced. A this observation asks for a mechanistic explanation for the parallel, chromatinbased mechanism to achieve devel targeting process. In recent years, work from plants and opmentally controlled silencing programs is associated the fission yeast Schizosaccharomyces pombe have estab with Polycomb group (PcG) proteins, which accomplish lished that many of the heterochromatin components in targeted gene silencing using an H3K27me3based mech these systems are associated with RNAdirected tran anism. However, this review will primarily focus on scriptional silencing [19]. In these systems, RNA tran mechanisms associated with HP1a targeting. Our discus scribed from repetitive, heterochromatic loci is processed sion of “heterochromatin” will be in reference to consti into small RNAs that ultimately become the targeting sig tutive, HP1adependent heterochromatin unless other nal for heterochromatin assembly. Such a targeting mech wise specified. In Drosophila, heterochromatin domains anism, in which the targeting signal is generated from include the pericentric heterochromatin flanking all cen heterochromatin (the target) itself, allows plasticity. This tromeres, the Telomere Associated Sequences (TAS) is thought to be necessary to accommodate imprecision adjacent to the HeTA and TART elements that make up during DNA replication or following new TE invasions the telomeres, and the bulk of the small fourth chromo that change the system’s DNA composition, while ensur some (Muller F element) [13]. ing functional precision (faithful heterochromatin assem A classic and commonly used assay to dissect the cis bly). and transacting factors involved in heterochromatic Schizosaccharomyces pombe, a model organism for silencing in Drosophila (among other systems) involves which RNAdirected transcriptional silencing is well positioneffect variegation (PEV), first observed in described, serves as an excellent example of how cis Drosophila melanogaster by Herman Muller in 1930. sequence determinants can work with transacting factors Following Xray mutagenesis, Muller recovered fly lines to assemble heterochromatin at repeats, generally rem (termed wm, white mottled) that had a variegating, red nants of transposable elements (TEs). Targeting of the interspersedwithwhite pattern across the fly eye, rather HP1 family protein Swi6 and the H3K9 HMT Clr4 than the normal solid red (or completely
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