Multiple SET Methyltransferases Are Required to Maintain Normal Heterochromatin Domains in the Genome of Drosophila Melanogaster

By Brower-Toland, Brent; Riddle, Nicole C. et al. | Genetics, April 2009 | Go to article overview

Multiple SET Methyltransferases Are Required to Maintain Normal Heterochromatin Domains in the Genome of Drosophila Melanogaster


Brower-Toland, Brent, Riddle, Nicole C., Jiang, Hongmei, Huisinga, Kathryn L., Elgin, Sarah C. R., Genetics


ABSTRACT

Methylation of histone H3 lysine 9 (H3K9) is a key feature of silent chromatin and plays an important role in stabilizing the interaction of heterochromatin protein 1 (HP1) with chromatin. Genomes of metazoans such as the fruit fly Drosophila melanogaster generally encode three types of H3K9-specific SET domain methyltransferases that contribute to chromatin homeostasis during the life cycle of the organism. SU(VAR)3-9, dG9a, and dSETDB1 all function in the generation of wild-type H3K9 methylation levels in the Drosophila genome. Two of these enzymes, dSETDB1 and SU(VAR)3-9, govern heterochromatin formation in distinct but overlapping patterns across the genome. H3K9 methylation in the small, heterochromatic fourth chromosome of D. melanogaster is governed mainly by dSETDB1, whereas dSETDB1 and SU(VAR)3-9 function in concert to methylate H3K9 in the pericentric heterochromatin of all chromosomes, with dG9a having little impact in these domains, as shown by monitoring position effect variegation. To understand how these distinct heterochromatin compartments may be differentiated, we examined the developmental timing of dSETDB1 function using a knockdown strategy. dSETDB1 acts to maintain heterochromatin during metamorphosis, at a later stage in development than the reported action of SU(VAR)3-9. Surprisingly, depletion of both of these enzymes has less deleterious effect than depletion of one. These results imply that dSETDB1 acts as a heterochromatin maintenance factor that may be required for the persistence of earlier developmental events normally governed by SU(VAR)3-9. In addition, the genetic interactions between dSETDB1 and Su(var)3-9 mutations emphasize the importance of maintaining the activities of these histone methyltransferases in balance for normal genome function.

KEY constituents of heterochromatin include the structural protein HP1 and histoneH3 methylated on lysine 9 (H3K9me) (Grewal and Elgin 2002). The formation of heterochromatin inmost eukaryotes, from the unicellular fission yeast to humans, involves an orthologof theDrosophilaSU(VAR)3-9 protein, which is an H3K9-specific methyltransferase (Schotta et al. 2003b). However, most metazoan genomes encode members of at least three H3K9-specific SET domain methyltransferase families, including SU(VAR)3-9, G9a, and SETDB1 (Huisinga et al. 2006). Mammalian G9a and SETDB1 methyltransferases have important roles in euchromatic gene regulation (Schultz et al. 2002; Tachibana et al. 2002). The importance of these methyltransferases for heterochromatin formation is less well understood. Likewise, the contribution of each of theseenzymes togenomewideH3K9mehomeostasis is not well documented. The Drosophila melanogaster genome encodes one representative of each H3K9-specific SET methyltransferase family, namely SU(VAR)3-9, dG9a, and dSETDB1 (Stabell et al. 2006a,b; Seum et al. 2007a). We have utilized this system to study the combined functionand interaction of the three enzymes and their contribution to chromatin homeostasis in a metazoan.

In most species, heterochromatin is present in the regions around centromeres and at telomeres (Dillon 2004). This is also true in Drosophila, with the additional presence of heterochromatin throughout the length of the small fourth chromosome [also referred to as the "dot" chromosome because of its appearance in mitotic nuclei (Locke and McDermid 1993)]. The heterochromatic character of the fourth chromosome, as well as pericentric regions, is apparent from cytological preparations showing enrichment for HP1 at those locations ( James and Elgin 1986). H3K9me2-3 (di- and trimethylation) shares the same distribution as HP1 in Drosophila heterochromatin, and SU(VAR)3-9 is codistributed with HP1 and H3K9me2-3 at pericentromeric and fourth chromosome locations (Schotta et al. 2002). Despite this similarity in distribution, SU(VAR) 3-9 is not solely responsible for heterochromatic H3K9 methylation in Drosophila; in Su(var)3-9 mutants, pericentric H3K9me is diminished, but in the fourth chromosome H3K9me appears unchanged (Schotta et al. …

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Multiple SET Methyltransferases Are Required to Maintain Normal Heterochromatin Domains in the Genome of Drosophila Melanogaster
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