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Histone Methyltransferase Signaling Pathway


Figure1. Histone methyltransferase signaling pathway

Histone methyltransferase overview

DNA and histones (H2A, H2B, H3, H4, H1) and some other proteins are combined and repeatedly folded and entangled to form a concentrated chromosome. Epigenetic modifications usually include DNA methylation and histone modification and RNA modification, while histone modifications include histone acetylation, phosphorylation, methylation, and ubiquitination. Most of the modifications are located at the N-terminus of histones. These modifications can affect the affinity of histones to DNA and change the state of chromatin. It can also affect the binding of transcription factors to DNA sequences and has a DNA-like genetic code for the regulation of gene expression, so it is called "histone code". Histone methylation refers to the occurrence of N-terminal arginine or lysine in H3 and H4 histones. Methylation at the residue of the amino acid is mediated by histone methyltransferase. The function of histone methylation is mainly reflected in heterochromatin formation, gene imprinting, and X chromosome inactivation and in terms of transcriptional regulation, 24 histone methylation sites are currently found, of which 17 are in lysine and the other 7 are in arginine. Lysine may be monomethylated, dimethylated, and trimethylated.

Histone methyltransferase family

The Su(var) 3-9 protein is the first histone lysine methyltransferase found in Drosophila, with a conserved SET domain-containing approximately 110 amino acids and being a plant ribulose diphosphate. Enzymes like Su(var)3-9 in mammals are SUV39H1 and SUV39H2, and in yeast Su(var) 3 -9 is like Clr4. These four enzymes only catalyze H3K9 methylation, while another methyltransferase G9a in mammals can not only catalyze H3K9 methylation but also catalyze H3K27 methylation. To found more methyltransferases, structural analysis methods are used to compare the currently known protein structures, and it is found that SET domain-associated proteins can be divided into four families, SET1, SET2, SUV39, and RIZ. Many of them have the function of histone methyltransferase, in which different enzymes catalyze the methylation of different lysine sites. So far, dozens of lysine methyltransferases and two major classes have been discovered. The first type of PRMT catalyzes the formation methylarginine and asymmetric dimethylarginine; the second type of PRMT catalyzes the formation of mono methylarginine and symmetric dimethylarginine. PRMT family includes PRMT1, PRMT3, RMT1/HMT1, PRMT4 /CAMR1, and PRMT5. Among them, only PRMT5 belongs to the second category, and the rest belong to the first category.

Histone methyltransferase signaling pathway

  1. Histone methyltransferase signaling pathway cascade
    Histone methylation and heterochromatin formation: methyltransferases encoded by two genes, suv39hl and suv39h2, play an important role in the formation of heterochromatin. The methylation of the H3K9 locus in fission yeast can separate euchromatin and heterochromatin in specific regions. In the process of forming heterochromatin, the interaction between Su(var)3-9 and heterochromatin 1 (HP1) controls the localization of the protein. Some scholars have proposed a model for the formation of heterochromatin: first, histone deacetylase makes H3K9, H3K14 deacetylation, then SUV39Hl methylation of H3K9. H3K9 methylation then affects DNA methylation, followed by methylation of H3K9 as a binding site to recruit HP1 protein localization, and finally, HP1 localizes in the heterochromatin region of the interphase nucleus, involves in the formation of high-level chromosome structures, and finally forms heterochromatin multimers. Histone methylation and gene imprinting: Gene imprinting refers to a pair of alleles. One from the father and one from the mother, and any of which is in a state of inhibition, is called a genetic imprint. Histone methyltransferase plays an important role in gene imprinting. Lack of histone methyltransferase leads to loss of gene imprinting. During embryonic stem cell differentiation, Xist expression is related to H3K27me3, H4K20me1, and DNA methylation. Embryonic tissue random loss of the activity of the X chromosome is controlled by DNA methylation, and the maintenance of the extracorporeal tissue for the imprinted X chromosome inactivation depends on the function of Eed and the expression of Xist, independent of DNA methylation. Thus, X chromosome inactivation and genomic imprinting may be caused by the same mechanism, including histone methylation and ncRNA. Histone methylation and transcriptional regulation: Histone methylation occurs on lysine and arginine residues. The study found that histone lysine methylation plays an important role in chromatin formation and gene expression. Recently, it was found that during transcription, the PAF transcriptional elongation complex can recruit Set1 and Set2 two histone methyltransferases to mRNA. The coding region regulates gene transcription. In this process, RNA polymerase II exhibits a terminal phosphorylation state, so this phosphorylated RNA polymerase is a histone methyl group. Arginine methylation: Arginine methylation occurs on histones H3 (R2, R17, R26) and H4 (R3), either monomethylated or double basicization; the latter can exhibit symmetric dimethylation or asymmetric dimethylation. Arginine methylation activates gene expression. Histone arginine methyltransferase is recruited as a synergistic activator promoter region of the gene. This enzyme belongs to histone methyltransferase. The methylation of H3K4 must be ubiquitinated at position 123 of lysine at H2B, but H3K36 methylation is not subject to this limitation. This is mainly because H2KK123 can be recruited after ubiquitination of H2BK123. The base transferase Set1 and Set1 can also recruit the PAF1 elongation complex. When the 5-position serine in the C-terminal domain of RNA polymerase II is phosphorylated, it can be used together with this extended complex to initiate gene transcription. The transferase Dot1 can also be recruited into the complex to initiate transcription. The study also found that Ubp8, as a component of the SAGA complex, acts to remove ubiquitination, resulting in deubiquitination after H3K4 methylation. Thus, H3K36 methyltransferase Set2 can be recruited to activate gene transcription when H3K36 methylation occurs simultaneously with serine phosphorylation of RNA polymerase II CTD region. It is speculated that H3K4 methylation may be an early event of transcription. The above is a study done in Saccharomyces cerevisiae. Although there are similar reports on H3K4 methylation in multicellular animals, this Decoration is very complex in multicellular animals, and specific functional needs further study.
  2. Pathway regulation
    The methylation of histone H3K9, H3K27, H3K79, and H4K20 sites plays a transcriptional repressing role. H3K4 methylation is a marker of gene transcriptional activation and is regulated by different methyltransferases. The study found that PC3 cells histone H3K4methylation expression is low, while H3K9 is highly expressed; PHI can up-regulate histone H3K4 methylation level and inhibit H3K9 methylation level. PHI can precisely regulate histone methylation expression. Activation of transcription factors activates transcription of genes, thereby inhibiting proliferation of PC3 tumor cells and inducing apoptosis. PHI can regulate the methylation status of H3K4 and H3K9 in the classical histone deacetylase inhibitor trichostatin, regardless of whether PHI itself has histone methyltransferase activity or other pathways. Activation or recruitment of histone methyltransferase changes the methylation status of H3K9 and H3K4, and the specific mechanism remains to be further studied. Histone methyltransferase inhibitors (HMTis): HMTis have been found to target histone lysine methyltransferases (HKMTs) such as G9a, GLP1, and DOT1L. BIX01294 was the first HKMT-specific inhibitor to be discovered. BIX01294 binds to G9a and GLP1, but its low affinity and cytotoxicity limit its use. E27 and UNC321 are generation 2 inhibitors whose chemical structure introduces a 7-alkoxy amino group, and such covalent modification increases the affinity for the enzyme. UNC638 also contains a 7-alkoxyamine group, which has higher cell efficiency, lower toxicity and better application prospects. Other small molecule inhibitors, such as AZ505, efficiently and specifically inhibit the expression of the oncoprotein SMYD2 by binding to the substrate binding site of HKMTs. EPZ004777 is an analog of SAM that competitively binds to SAM with DOT1L and has an inhibitory effect on DOT1L. Compounds that bind to SAM include the fungal metabolites of chitin and carprofen. In addition to HKMTis, potent inhibitors of protein arginine methyltransferases (PRMTs) have also been discovered, such as the amine analog of adenosylmethionine, AzaAdoMet3, and inhibitors of purine or pyrazole.
  3. Relationship with disease
    The SET domain exists in many human genes involved in tumorigenesis. Over the past 10 years, it has been found that most of the genes with this domain function as tumor suppressors. Recently, histone methyltransferase has also been found to have a SET domain. It is natural to speculate whether histone methyltransferase has a tumor suppressor function. RIZ1 (PRDM2) has H3K9 methyltransferase activity. Studies have found that in certain tumors, such as breast cancer, liver cancer, colon cancer, neuroblastoma, myeloma, lung cancer, and bone tumors, the gene is mutated and loses its activity, and its inactivation causes the cell cycle of G2-M phase to prolong and inhibit apoptosis. Transferase may have a tumor suppressor function. In addition, methylation of H4R3 affects leukemia cell differentiation. MLL1 methyltransferase mutations are associated with multiple types of leukemia. In prostate cancer, lymphoma, and breast cancer, high expression of EZH2 methyltransferase indicates that histone methyltransferase abnormality may be involved in solid tumorigenesis.

References:

  1. Sun Y W, Tee C S, Ma Y H, et al. Attenuation of Histone Methyltransferase KRYPTONITE-mediated transcriptional gene, silencing by Geminivirus. Scientific Reports. 2015, 5:16476.
  2. Dudakovic A, Camilleri E T, Xu F, et al. Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2. Journal of Biological Chemistry. 2015, 290(46):27604.
  3. Zagni C, Chiacchio U, Rescifina A. Histone methyltransferase inhibitors: novel epigenetic agents for cancer treatment. Current Medicinal Chemistry. 2013, 20(2).
  4. Rivière L, Gerossier L, Ducroux A, et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. Journal of Hepatology. 2015, 63(5):1093-1102.
  5. Wen L, Fu L, Guo X, et al. Histone methyltransferase Dot1L plays a role in postembryonic development in Xenopus tropicalis. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology. 2015, 29(2):385-93.

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