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Interaction of SET Domains with Histones and Nucleic Acid Structures in Active Chromatin

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Interaction of SET Domains with Histones and Nucleic Acid Structures in Active Chromatin Clin Epigenet (2011) 2:17–25 DOI 10.1007/s13148-010-0015-1 CARCINOGENESIS Interaction of SET domains with histones and nucleic acid structures in active chromatin Wladyslaw A. Krajewski & Oleg L. Vassiliev Received: 15 July 2010 /Accepted: 16 November 2010 /Published online: 14 January 2011 # Springer-Verlag 2011 Abstract Changes in the normal program of gene The accumulated data suggest that many diseases and expression are the basis for a number of human diseases. metabolic disorders are caused by altered patterns of gene Epigenetic control of gene expressionisprogrammedby expression (Kaminsky et al. 2006; Perini and Tupler 2006; chromatin modifications—the inheritable “histone Maekawa and Watanabe 2007). The chromatin-templated code”—the major component of which is histone processes are controlled by a complex pattern of posttrans- methylation. This chromatin methylation code of gene lational modifications of the flexible N-terminal tails of activity is created upon cell differentiation and is further histone proteins, including methylation, acetylation, phos- controlledbythe“SET” (methyltransferase) domain phorylation, ubiquitination, etc., which comprise the inher- proteins which maintain this histone methylation pattern itable “histone code” of gene function (Marmorstein and and preserve it through rounds of cell division. The Trievel 2009), although the effects of the histone code may molecular principles of epigenetic gene maintenance are depend on the particular situation (Lee et al. 2010). essential for proper treatment and prevention of disorders Chromatin activity is largely determined by the methylation and their complications. However, the principles of status of specific lysine and arginine residues in the N epigenetic gene programming are not resolved. Here we termini of histones H3 and H4 (Li et al. 2007; Shilatifard discuss some evidence of how the SET proteins 2008). For example, methylation of K4, 36, and 79 in determine the required states of target genes and maintain histone H3 promotes gene activation, while methylation of the required levels of their activity. We suggest that, H3 K9, 27, and H4 lys20 is associated with gene silencing. along with other recognition pathways, SET domains can The knowledge of epigenetic gene regulatory principles is directly recognize the nucleosome and nucleic acids essential for developing targeted therapies. intermediates that are specific for active chromatin With the exception of Dot1 which methylates H3 K79 regions. (van Leeuwen et al. 2002), the methylation of histone lysines for chromatin activity and silencing is conferred, Keywords Chromatin . Gene expression . Histone respectively, by the Trithorax and Polycomb group histone methylation methyltransferases, containing a conserved 130-amino-acid catalytic “SET” domain [Su(var), Enhancer of zeste, W. A. Krajewski (*) Trithorax] (Qian and Zhou 2006). The SET domain is a Institute of Developmental Biology, paradigm for both positive and negative regulators of Russian Academy of Sciences, chromatin activity. Less well-conserved pre- and post-SET ul. Vavilova 26, sequences may flank SET domains at N and C boundaries, Moscow 119334, Russia e-mail: [email protected] respectively. The SET domain proteins assume full control on the maintenance of chromatin lysine methylation O. L. Vassiliev through rounds of cell divisions, after the gene activity Shemyakin Institute of Bioorganic Chemistry, patterns have been established in early embryogenesis by a Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, cascade of maternal and zygotic transcription factors Moscow 437, Russia (Breiling et al. 2007). However, it is not fully understood 18 Clin Epigenet (2011) 2:17–25 how SET domain proteins can “decide” on the required in core histones. For example, Set1, Trithorax and MLL1/4 states of gene activity in a tissue-specific manner, how SET methylate H3-K4, Su(var)3–9 and Suv39h1 methylate H3-K9, proteins can initially recognize their target genes, and the E(z) and Ezh2 methylate H3-K27, Set2 and HPBD methylate way this “recognition” is transmitted to progeny cells. H3-K36, PR-Set7/8, and Suv4h20 methylate H4-K20. Some The molecular mechanisms behind SET-domain recogni- proteins methylate multiple sites. For example, Ash1 can tion of chromatin activity states are essential for understanding methylate H3-K4, -9, and H4-K20 (Gregory et al. 2007), the molecular etiology of epigenetic-related disorders. The NSD1-3 can methylate H3-K36 and H4-K44 (Li et al. 2009). best studied example is cancer (Albert and Helin 2010), HKMTs often function within multiprotein complexes. For although a number of other diseases also result from aberrant example, Trithorax functions within the acetylation complex, chromatin methylation patterns. For example, it has been TAC1 (Petruk et al. 2001) and Polycomb Repressive shown that correct functioning of islet beta cell depends on complexes type 2 (PRC2) are based around the Ezh2 [the E the methyltransferase Set7/9 which is implicated in main- (z) in Drosophila] methyltransferases (Schwartz and Pirrotta taining the active chromatin status of genes required for 2007). Isolated HKMT complexes may include tens of glucose-stimulated secretion of insulin (Deering et al. 2009). different transcription factors, like the MLL1 complex, An aberrant histone methylation pattern may be a major reflecting the complexity of the HKMT interactions in vivo underlying mechanism for sustained proinflammatory (Nakamura et al. 2002), although only a few core components phenotype of diabetic cells. The SET7/9 protein recognizes may be critical for HKMT functional activity (like the Wdr5, and preserves the correct methylation states of K4 in histone RbPB5, Ash2, and Menin subunits of MLL1; Dou et al. H3 in chromatin of NF-kappa B-dependent inflammatory 2006). genes, the correct functioning of which is critical for Data in the literature suggest several, not mutually preventing the progression of diabetes and the metabolic exclusive, possibilities of how SET proteins may recognize syndrome (Li et al. 2008). Trimethylation of histone H3-K9 their chromatin targets. by Suv39h1 is essential in preventing the pre-activated state (a) SET-domain proteins can recognize their target genes of diabetic vascular smooth muscle cells (Villeneuve et al. through direct or indirect interaction with site-specific 2008). Methylation of histone H3 controls the expression of chromatin-binding factors, including factors recogniz- insulin (Cavener 2009). The tissue-specific heritable aberra- ing specific histone modifications. tions in histone methylation pattern could be a reason for the propagation of the trans-generational insulin-resistant pheno- Thus, human MLL1/MLL2 methyltransferases can bind type in gestational diabetes (Devaskar and Thamotharan activated estrogen receptor-α through the associated tumor 2007). The Ezh2 methyltransferase is implicated in the suppressor Menin (Dreijerink et al. 2006), TRR, the major maintenance of normal pancreatic beta cell proliferation, Drosophila H3-K4 methyltransferase, can be targeted to likely by preserving histone H3 trimethylation at the Ink4a/ ecdysone-responsive promoters through direct association Arf locus in islet beta cells, thus preventing beta cell with ecdysone nuclei receptor (Sedkov et al. 2003), MLL1 regenerative failure and diabetes (Chen et al. 2009; can associate with E2F transcription factor 6 (Dou et al. Villeneuve et al. 2008). In addition, the Ezh2 protein is 2005), Trithorax and MLL methyltransferases may be also likely to be involved in formation of cancerous targeted to chromatin through association with heat shock tissues, including prostate and breast cancers (Simon and proteinHSP90(Tariqetal.2009), PRC2 complexes can Lange 2008). Deregulation by MLL1, the human homolog be site-specifically anchored to DNA by PHO/PHO-like/ of Drosophila Trithorax, results in lymphoid and myeloid YY-1 DNA-binding proteins (Brown et al. 2003), etc. The acute leukemias (Cosgrove and Patel 2010). Epigenetic recruitment of SET-domain proteins may also involve alterations are also implicated in the development of direct interactions of HKMTs with specific DNA sequen- cardiac hypertrophy, ischemia (Maekawa and Watanabe ces; for example, the interaction of MLL1 with DNA 2007; Granger et al. 2008; Kaneda et al. 2009), rheumatic through CXXC domain, which binds to non-methylated arthritis (Strietholt et al. 2008), autoimmune disease (Szyf CpG DNA sites (Cierpicki et al. 2010), could contribute to 2010), asthma (Schwartz 2010), and other diseases (Perini stable association of MLL1 with HoxA9 genes (Milne et and Tupler 2006; Maekawa and Watanabe 2007). There al. 2010). Direct interaction of NSD1, -2, -3 and PR- are many of such studies, but their practical implications SET7/8 SET domains with DNA may be essential for are still limited by insufficient understanding of the methylation specificity and activity of these enzymes (Li principles of how the SET-domain proteins recognize, et al. 2009). maintain, and propagate the states of chromatin activity to The recruitment of SET-domain proteins may implicate descendant cells. the recognition of site-specific histone modifications and Most of the SET-domain methyltransferases (HKMTs) histone variants. For example, PHD motifs of MLL1 and can mono-, di-, and trimethylate one specific lysine residue Trithorax proteins can recognize histone H3 trimethylated at Clin Epigenet (2011) 2:17–25 19 lysine 4 and thus contribute to the stable chromatin association
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