Advances in histone methyltransferases and histone demethylases

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1 [Chinese Journal of Cancer 27:10, ; October 2008]; 2008 Sun Yat-Sen University Cancer Center Review Advances in histone methyltransferases and histone demethylases Xi Wang and Wei-Guo Zhu Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing, P.R. China Key words: epigenetics, histone methyltransferase, histone demethylases Histone modification as one of the key epigenetic regulation mechanisms plays critical roles in various biological processes, including regulation of chromatin structure dynamics and gene expression. Both histone methyltransferase and histone demethylases contribute to the establishment and maintenance of different histone methylation status. The effectors which can recognize histone methylated sites build a relationship between these modifications and their down stream processes. This review summarized recent advances in histone methyltransferases and histone demethylases. The basic compositional unit of chromatin is a nucleosome, consisting of a histone octamer surrounded by a 146 bp DNA. The histone octamer is composed of a pair of each of the subunit: H2A, H2B, H3, and H4. Usually, the N-terminal of histone can be modified by various manners, such as phosphorylation, acetylation, methylation, ubiquitination, and so on, which could influence the chromosomal structure and the transcriptional process. Modifications at these regions can independently or coordinately with others act on the downstream process. Methylation of histone usually occurs at the lysine or arginine residue at the N-terminal of histone, which leads to multiple effects including activation or inhibition of transcription (Tables 1 4). Methylated histone is considered to work through specifically recognizing the effector protein of the methylated residues. These effector proteins have the bridging effect, some of which are possibly the key molecules for some important biological processes. Therefore, they can regulate the functions of chromatin. Because each lysine residue has three forms of methylation, monomethylation, dimethylation, and tri-methylation (the arginine residue has the forms of monomethylation, symmetric dimethylation, and asymmetric dimethylation), and nearby residues can form different methylation combinations, thus, the various combination of different effector proteins may induce multiple biological effects. 1-4 *Correspondence to: Wei-Guo Zhu; Department of Biochemistry and Molecular Biology; Peking University Health Science Center; Beijing P.R. China; Tel.: ; Fax: ; zhuweiguo@bjmu.edu.cn Submitted: 06/23/08; Revised: 07/16/08; Accepted: 07/16/08 This paper was translated into English from its original publication in Chinese. Translated by: Hua He on 09/25/08. The original Chinese version of this paper is published in: Ai Zheng (Chinese Journal of Cancer), 27(10); Previously published online as a Chinese Journal of Cancer E-publication: Although methylation is recognized as a stable process of modification, recent studies on antagonistic methylation or the removal of methylation have discovered arginine deiminase as the antagonist for arginine methylation, and amine oxidase and hydroxylase for the removal of lysine and arginine. Therefore, the activities between methylase and demethylase, which are involved in the downstream process and closely related to histone methylation, are dynamically adjusted. Histone Methyltransferases Histone methylation includes the methylation of arginine and lysine, which are usually thought to occur at the N-terminals of H3 and H4. The methylation of arginine is primarily catalyzed by some members of the protein arginine methyltransferase (PRMT) family. Cofactor associated arginine methyltransferase (CARM1) and PRMT1 can catalyze arginine to produce monomethylation and asymmetric dimethylation, which are in relation to gene activation. PRMT2 can catalyze arginine to produce monomethylation and symmetric dimethylation, which are in relation to the gene inhibition. CARM1 primarily methylates H3R2, H3R17, H3R26, and H2A, while PRMT1 methylates H4R3 and PRMT5 methylates H3R8 and H4R3. 5 Lysine methylation of histone is primarily completed by methyltransferase with the structure of the Supressor of variegation-enhanser of zeste-trithorax (SET) domain. It is reported that Dot1 of yeast and DOT1L of mammalian origin can catalyze methylation by the structure of the non-set domain. 6 Usually, the methylation of H3K4, H3K36, and H3K79 is closely correlated to the activation domain of chromatin, while the methylation of H3K9, H3K27, and H4K20 is related to the silent domain. The methylase for H3K4 belongs to of the protein family of mixed lineage leukemia (MLL), including MLL1, MLL2, MLL3, MLL4, SET1A, SET1B, and ASH MLL1 and MLL2 are important in maintaining the longterm expression of Hox gene during the development. Knock-out the MLL1 SET domain gene in rats results in phenotypic defects of rats, suggesting that H3K4 methylation is important in regulating genetics and phenotypes. 13 In addition, the rearrangement of MLL1 gene are found to associate with leukemia in children and adults. MLL family methyltransferase exists in the form of a polyprotein complex to exert its effects. The major common complexes of the MLL family include WDR5, RbBP5, and ASH2 7,8,10,11,14 Furthermore, Set9 is active in histone H3K4 methylation, even though such activity is only found in the in vitro experiment. 15 Set9 takes participation in catalyzing p53 methylation Chinese Journal of Cancer 2008; Vol. 27 Issue 10

2 H3K9 methylation is functionally important in the X-chromosome silence, heterochromatin formation, DNA methylation, and transcriptional regulation. The methyltransferases for H3K9 methylation are SUV39H1, SUV39H2, Eu-HMTase/GLP, G9A, ESET/ SETDB1, and RIZ1, whose catalyzing substrates and products are different. SUV39H1 and its homolog in fission yeast, Clr4, were the first discovered specific H3K9 histone methyltransferases. 17 SUV39H2, whose expression was tissue-specific, was discovered later. 18 Tri-methylation of H3K9 catalyzed by SUV39 primarily acts on heterochromatin and participates in the formation of heterochromatin and transcriptional inhibition. 19 Also, SUV39 exists in the promoter region of euchromatin to inhibit gene expression. 20 G9A primarily catalyzes dimethylation of H3K9, thus to inhibit the gene expression in euchromatin. 21 Currently, it has been found that many transcriptional factors can recruit G9A to deactivate their downstream gene expressions. Deactivation of G9a in rats can cause growth retardation and fetal death at an early stage, suggesting that G9a-mediated H3K9 methylation in the euchromatin domain has contributed to the early development of fetus. 22 In addition, H3K9 methylation mediated by G9a can be served as the platform for the binding of HP1α, β and γ, resulting in the interaction between DNMT1 and HP1 to induce an amount increase of methylated DNA. 23 Treatment with depsipeptide decreases the expressions of G6A and SUV39H1, which further causes a collective decrease in the level of H3K9me2/me3 gene at the promoter region. These changes would cause a drop of HP1 and DNMT1 recruitment and result in DNA demethylation. 24 Another active histone methyltransferase at the euchromatin domain is Eu-HMTase1/GLP, which is related to E2F-6, Mga, and Max. It may be potentially useful during the resting period, whereas reactive genes of E2F- and Myc- are silenced. 25 In the same time, GLP can form a heteropolypeptide complex with G9a, and together they could act on H3K9 methylation. 26 ESET/ SETDB1 causes tri-methylation of H3K9 at the euchromatin domain, 27 and form a complex with HDAC1/2 histone acetyltransferase. SETDB1 can bind with three major types of transcriptional factors: ATFa from CREB and ATF family, ERG from ETS family, and KAP-1 of KRAB-ZFP assisting inhibitors. 27,28 SETDB1 can also bind or form complexes with HP1, MBD1, and DNMT3A/B, as well as participate in the regulation of transcriptional activities. 29,30 Besides, a tumor inhibitory factor, RIZ1, has also been reported to possess methyltransferase activity to catalyze H3K9 methylation. 31 EZH2 catalyzes H3K27 methylation and form the polycomb restriction complex (PRC) with other PcG proteins. EZH2 has an inhibitory effect on gene transcription and is extremely important in the fetal development and cellular differentiation. 32,33 SET2, SYMD2, and NSD1 can mediate H3K36 methylation. In S. cerevisiae, set2 is related to RNAPII in the elongation process. 34 The methyltransferase activity of Symd2 histone is related to the encoding region acetylation of activated genes mediated by Sin3A. Symd2 could inhibit cell proliferation by regulating the structure of chromatin. 35 NSD1 is recognized to have important functions in the process of development and found mutated in acute myeloid leukemia (AML), multiple myeloma (MM), and lung cancer. Deregulation of methylated H3K36 is carcinogenic and is related to the inhibition of NSD1-mediated Hox-A transcription. 36 DOT1L, a H3K79 methylase, is so far the only known lysine methyltransferase without the SET structural domain. DOT1L can be recruited to the Table 1 Table 2 Histone arginine methyltransferases Histone arginine demethylases target gene of MLL-AF10 fusion protein, such as HoxA9. H3K79 methylation by DOT1L can up-regulate the expression of HoxA9, resulting in leukemic transformation. 37 Histone Demethylases Protein-arginine deiminase type-4 (PADI4) can transform the methylated arginine into citrulline. However, because PADI4 does not remove the methyl domain, technically, it is not a real demethylase 38,39 PADI4 can specifically act on the substrate of monomethylation and result in the appearance of arginine deiminase in H3R2, H3R8, H3R17, H3R26 and H4R3. 38 Recruitments of histone methyltransferases PRMT1 and CARM1 to the promoter regions of these genes induced by hormone could expedite methylation of the arginine residue and activate gene transcription. Later, PADI4 is recruited to the promoter regions of the above mentioned genes and it transforms the methylated arginine residue to citrulline to detach RNA polymerase II from its targeted gene. 38, 39 In addition, re-methylation of the arginine residue after deimination could regulate the activation and deactivation of hormone-induced gene expressions. Besides deimination, a real methyltransferase of arginine has been discovered. Jumonji domain-containing protein 6-A (JMJD6) is a 2-ketoglutarate-dependent dioxygenase with iron in the structural domain of jumonji-c (JmjC), which could demethylate H3R2 and H4R3. 40 Lysine-specific histone demethylase 1 (LSD1) is a histone demethylase whose cofactor is FAD and whose products are formaldehyde and a non-methylated lysine residue. It could form a complex with proteins, such as Co-REST, BHC80, and HDAC1/2 41 to synergically exert biological effects. LSD1 can recognize and demethylate H3K4me1 and H3K4me2. Co-REST is a chromatin-related transcriptional inhibitor. It can change the substrate of LSD1 when it is formed a complex with LSD1. 42,43 The Co-REST complex was firstly believed to inhibit the transcription of neuronal genes in nonneuronal cell lineages 44 and LSD1 could cause H3K4 demethylation of the Co-REST targeted genes to induce transcriptional inhibition. 45 Furthermore, the binding of LSD1 with the testosterone receptor can transform LSD1 into H3K9 demethylase to induce hormone-dependent transcription 46,47 Also, LSD1 plays a similar role in regulating the testosterone-dependent transcription Chinese Journal of Cancer 297

3 Table 3 Table 4 Histone lysine methyltransferases Histone lysine demethylases The protein family with the JmjC domain is another class of demethylases whose cofactors are Fe (ii) and α-ketoglutarate. The family members can demethylate multiple points at H3K4, H3K9, H3K36, and so on, which show wide effects. JmjC domain-containing histone demethylation protein 1A (JHDM1A) is a specific demethylase for H3K36me2 and H3K36me1. Methylation of H3K36 usually occurs at the transcriptional region of genes with the help of H3K36 methyltransferase and Po1 II. The methylation of H3K36 in the transcriptional region of activated genes could recruit transcriptional inhibitors to prevent the initiation of intragenic transcription Although there are no reports on the correlations of JHDM1A to chromatin and their recruitments, JHDM1 may possibly have the binding potential to the modification sites for histone methylation, because it contains the chromatin-related domain, such as PHD. 1,2,52,53 JHDM2 (primarily JHDM2A and JHDM2B) is a specific demethylase for H3K9 and it can recognize H3K9me2 and H3K9me1. 47 Previous studies have shown that JHDM2C could interact with thyroid receptors, suggesting a role of JHDM2C in the regulation of transcription of nuclear hormone receptors. 54 In addition, testosterone receptors can bind to JHDM2A. With the existence of testosterone receptor ligands, JHDM2A is recruited to the targeted gene of the testosterone receptor to activate transcription; while the methylation level of H3K9 at the promoter region drops. 47 JHDM3A/JMJD2A can catalyze demethylation of H3K9me3/2 and H3K36me3/2, resulting in an accumulation of H3K9me1 and H3K36me1. 55 JMJD2B is related to heterochromatin formation, 56 and JMJD2C/GASC1 is highly expressed in some cell lines of esophageal squamous cell carcinomas. The inhibition of JMJD2C can weaken cell proliferation, which is possibly associated with reduced methylation of H3K9 and HP1 caused by JMJD2C demethylation. 57 JMJD2C, through its interaction with LSD1, also demethylates H3K9me1/2/3, and stimulates testosterone-dependent gene transcription. 58 On the other hand, JARID1A/RBP2 can catalyze demethylation of H3K4me3 and H3K4me Also, it can change the methylation status of H3K4 to regulate transcription. 59 JARID1B/PLU-1, a type of transcription inhibitors, are hyperactively expressed in breast cancer. 62 JARID1B-mediated demethylation of H3K4, by inhibiting the BRCA1 suppressor gene, has important impact on proliferation of breast cancer cells. 63 Additionally, the expression of JARID1B is up-regulated in prostate cancer, which is related to the testosterone receptor and its transcriptional activity. 64 JMJD3 298 Chinese Journal of Cancer 2008; Vol. 27 Issue 10

4 Table 5 Effectors and chromatin-related domains is also upregulated in prostate cancer, in metastatic prostate cancer in partivcular. 65 The JARID1C complex contains HDAC1/2, G9A, and the transcriptional inhibitor REST. It is believed that the JARID1C complex is related to inhibition on the neural system mediated by REST, because it can induce X-linked developmental retardation. 66 Furthermore, UTX, a specific H3K27 demethylase, has also been discovered. 67 Effector Proteins: Recognition of Histone Methylation Methylated histones may exert their effects through recruiting the downstream effector proteins to participate in many biological processes. At the same time, these effector molecules which have capabilities to bind with methylated histones have certain structural similarities known as chromatin-related domains, mainly including Chromo, Tudor, and MBT domains of Royal superfamily, PHD structural domain, WD40 repeats, and Ankyrin repeats (Table 5). However, the functional significances of proteins which can bind to methylated lysine or arginine residues are still unclear. In the MLL complex, WDR5, RbPB5, and ASH2 exist in the form of sub-complexes, but not directly bind to the SET structural domain of MLL1. WDR5 has a strong binding capability to H3K4me2, 68,69 and it helps to expose the side chain of H3K4 to be further methylated by methylase. 70 In addition, the MLL complex may consist of other subunits, such as the regulatory factor for cell proliferation HCF-1 and tumor inhibitory factor menin. 8,10,11,71 In the LSD1 complex, BHC80 can bind with non-methylated H3 to stabilize and enhance the demethylation effect of LSD1 on the downstream sequences. 72 It is proposed that WDR5 and BHC80, as the binding proteins for histone modification, have the major function in assisting and catalyzing, or at least stabilizing the enzymatic function of a complex. There are other effector proteins playing as links between histone modification and effects on the downstream sequences, such as ING2, which can recognize H3K4me3 to stabilize proliferation-related genes in the promoter region of the msin3a- HDAC1 complex during DNA damage, and inhibit the activated genes. Also, ING2 can interact with H3K4me3 to regulate cell response to stress. 2 53BP1 is the direct link between histone modification and DNA repair. 73 CHD1, through its interaction with H3K4me3, reveals a link between H3K4 and spliceosome which is beneficial to the maturation of pre-mrna. 74 HP1 is a bridge linked with various downstream processes, such as DNA methylation. 23 There are also proteins, such as JMJD2A, which can bind with H3K4me3, 75 and at the same time or not, catalyze H3K9me2/3 demethylation; 6 G9A and GLP can catalyze H3K9me1/2, as well as bind to H3K9me1/2. 77 These proteins are both effector proteins and demethylases. Further investigation is required to discover a potential link between the two or to explore whether they, as effector proteins, participate in other processes. The existence and discovery of histone methyltransferase, histone demethylase, and effector proteins of histone modification greatly increases our understanding of the correlations and complexities of histone modification and its effect on the downstream sequences. Interactions among various histone modifications on the same or different residues have been reported, such as methylation, acetylation, phosphorylation, ubiquitination, and so on. Cross talks in situ on the same residue are mostly exclusive, such as for H3K9 methylation and acetylation, 78 while modifications at different sites may be synergic or exclusive. Currently, most reports focus on the interactions among various modifications, including methylation, acetylation, and phosphorylation. For example, the combination of HP1 and H3K9me3, through binding with Chromo structural domain, can act together to form heterochromatin, while the phosphorylation of H3S10 can prevent the binding of HP1 and H3K9me3. 79,80 PRK1-mediated phosphorylation of H3T11 can speed up the demethylation of JMJD2C, which would further cause gene activation. 81 Similar interactions among modifications are discovered in non-histones, such as the K370, K372, and K382 methylation sites of p53 can interactively influence each other. 16,82,83 Furthermore, interaction of proteins or complexes can influence modification (such as methylation or demethylation) between different loci, as well as act as a link among various degrees of modification. These interactions can dynamically describe the order of histone modification in a biological process and the maintenance of modification status of histone. In the study on the irreversible inhibition of Oct-3/4 in early fetal development, there was a sign of acetylation in the promoter region of H3K9 and H3K14 of activated Oct-3/4. When differentiation starts, the interaction between inhibitors and Oct-3/4 causes immediate inhibition on the transcription and possibly trigger the binding of G9a and recruitment of HDAC, which further induces H3K9 and K14 deacetylation. This process leads to a stable inhibitory effect. 84 Histone modification Chinese Journal of Cancer 299

5 causes unavoidable changes in its downstream sequences, including specific recognition and binding with effector molecules, which may also involve dynamic triggering and transformation. The modified status and transcription of histones is one of the primary research directions. Interactions among histone methyltransferase, histone demethylase, effector proteins and transcriptional factors are the direct framework between transcriptional regulation and histone modification. Also, these processes include methylation status, maintenance of methylation by methylases and demethylases, and their changes. The major manifestations of histone modification and DNA damage on the downstream sequence rely on the bridging of the two aspects by effector proteins. In the mean time the effector proteins usually play a major role in the downstream processes. There are a few reports that reveal the effects of methylation, demethylase, and histone modification status in signal transduction pathways. In non-classical Wnt pathway, wnt-5a activates nemo-like kinase (NLK) to induce SETDB1 phosphorylation and form an inhibitory complex. The complex allows methylated H3K9 to inhibit PPARγ from activating its targeted gene. 85 This suggests that histone methylase and histone demethylase, and effectors protein could potentially and specifically participate in signal transduction pathways. They are also recruited by and interacted with important molecules of transduction pathways before finally regulate gene expressions of signal transduction pathways by changing the histone modification status in the promoter region of the gene. Acknowledgements Grants: National Natural Science Foundation of China (No , ); grants from the Ministry of Science and Technology of China (2005CB522403, 2006AA02Z101). References [1] Wysocka J, Swigut T, Xiao H, et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling [J]. 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