Role of Histone Methyltransferase in Fibrosis and Traditional Chinese Medicine Treatment： A Review / 中国实验方剂学杂志

Fibrosis， a tumor-like lesion between benign tissue and malignant tumor， mostly occurs in the liver， kidney， heart， lung， bone marrow and other organs and tissues. It can affect almost every organ and eventually induce multiple organ failure and cancers， seriously endangering human life. It will be of great importance to prevent cancer if the disease can be opportunely blocked in the fibrotic stage. The pathogenesis of fibrosis is still not completely clear. It is of great clinical significance to study the occurrence， development， and mechanism of fibrosis as well as to screen new therapeutic targets. Enhancer of zeste homolog 2 （EZH2） is mainly located in the nucleus and involved in the formation of the polycomb repressive complex 2. EZH2 is a methyltransferase which makes the lysine on position 27 of histone H3 （H3K27me3） undergo trimethyl modification induces gene silencing through classical or nonclassical actions， so as to inhibit or activate transcription. EZH2 plays a critical role in cell growth， proliferation， differentiation， and apoptosis， which is regulated by different targets and signaling pathways. EZH2 regulates the transformation of myofibroblasts and participates in the fibrosis of multiple organs. Recent studies have shown that EZH2 plays a role in fibrosis-related pathophysiological processes such as epithelial-mesenchymal transition， oxidative stress， and inflammation. EZH2 as the target of fibrosis， EZH2 inhibitors， and EZH2-related traditional Chinese medicine （TCM） formula and active compounds have gradually become hot research directions. EZH2 may be a powerful target for organ fibrosis. Exploring the structure， function， and distribution of EZH2， the role of EZH2 in fibrosis， the EZH2 inhibitors， and TCM formulas and active components targeting EZH2 has great meanings. This paper reviews the research progress in EZH2 and fibrosis， providing new ideas for the diagnosis， treatment， and drug development of fibrosis.

Progress of enhancer of zeste homolog 2 in hematological tumors / 白血病·淋巴瘤

The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase, which is widely studied in histone methylation modification. It can promote epigenetic gene silencing and mediate the occurrence of tumors through a variety of regulatory mechanisms. The gain-of-function and loss-of-function mutations of EZH2 have been confirmed in many cancers. At present, with the extensive attention paid to the regulatory role of EZH2 in epigenetic mechanism, the exact way in which EZH2 imbalance affects the pathogenesis of hematologic malignancies remains to be clarified. This article reviews the pathogenetic role of EZH2 in hematological tumors, and hope to find new targets for the prevention and treatment of hematological tumors.

Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line

During the tumorigenic process, cancer cells may become overly dependent on the activity of backup cellular pathways for their survival, representing vulnerabilities that could be exploited as therapeutic targets. Certain molecular vulnerabilities manifest as a synthetic lethality relationship, and the identification and characterization of new synthetic lethal interactions may pave the way for the development of new therapeutic approaches for human cancer. Our goal was to investigate a possible synthetic lethal interaction between a member of the Chromodomain Helicase DNA binding proteins family (CHD4) and a member of the histone methyltransferases family (SETDB1) in the molecular context of a cell line (Hs578T) representing the triple negative breast cancer (TNBC), a subtype of breast cancer lacking validated molecular targets for treatment. Therefore, we employed the CRISPR-Cas9 gene editing tool to individually or simultaneously introduce indels in the genomic loci corresponding to the catalytic domains of SETDB1 and CHD4 in the Hs578T cell line. Our main findings included: a) introduction of indels in exon 22 of SETDB1 sensitized Hs578T to the action of the genotoxic chemotherapy doxorubicin; b) by sequentially introducing indels in exon 22 of SETDB1 and exon 23 of CHD4 and tracking the percentage of the remaining wild-type sequences in the mixed cell populations generated, we obtained evidence of the existence of a synthetic lethality interaction between these genes. Considering the lack of molecular targets in TNBC, our findings provided valuable insights for development of new therapeutic approaches not only for TNBC but also for other cancer types.

Advances in histone epigenetic enzyme inhibitors based on proteomics / 药学学报

As an important component of nucleosomes on the chromatin of eukaryotic cells, histones play an important role in the development and progression of tumour diseases by regulating epigenetic post-translational modifications such as acetylation and methylation. In addition, development of inhibitors targeting methyltransferase and deacetylase provides novel therapeutic strategies for cancer treatment. Mass spectrometry-based proteomics can reveal the global changes of histone modifications under the action of drugs during disease progression, which in turn provides important support for revealing drug action mechanism, drug resistance mechanism, and investigating novel drug combination strategies. This article focuses on the progress and status of proteomic research on a variety of histone modifying enzyme inhibitors, including methyltransferase inhibitors and histone deacetylase inhibitors, which will help to understand the current and further utilization of proteomics in studying histone modifications.

Effects and molecular mechanism of histone methyltransferase enhancer of zeste homolog 2 on regulating sepsis-induced T cell dysfunction / 中华危重病急救医学

Objective:To investigate the effect and mechanism of histone methyltransferase enhancer of zeste homolog 2 (EZH2) on sepsis-induced T cell dysfunction.Methods:Twenty-four male C57BL/6 mice were divided into three groups randomly: sham operated group, sepsis model group [cecum ligation and puncture (CLP)+dimethyl sulfoxide (DMSO) group] and EZH2 selective inhibitor treated group (CLP+GSK126 group), with 8 mice in each group. Sepsis murine model was reproduced by CLP. CLP+DMSO group and CLP+GSK126 group were treated with DMSO or GSK126 (10 mg/kg) respectively right after surgery through intraperitoneal injection. The mice were sacrificed 24 hours after operation, and the mesenteric lymph nodes were collected. The expression of EZH2, apoptosis rates, cell proliferation marker ki-67 antigen positive T lymphocytes (ki-67 + cell), interferon-γ positive T lymphocytes (IFN-γ + cell), programmed death receptor-1 positive T lymphocytes (PD-1 + cell) and programmed death-ligand 1 positive T lymphocytes (PD-L1 + cell) were determined by flow cytometry. Results:Compared with sham operated group, the expression of EZH2 in T lymphocytes was up-regulated on mesenteric lymph nodes of CLP+DMSO group. Compared with CLP+DMSO group, the ratio of CD3 + T lymphocytes in CLP+GSK126 group was up-regulated (0.70±0.02 vs. 0.50±0.07, P < 0.01), indicating that the EZH2 inhibitor could increase the number of T lymphocytes in lymph nodes of septic mice; the ratio of ki-67 + cells in CD4 + and CD8 + T lymphocytes in CLP+GSK126 group was increased (CD4 +: 0.74±0.05 vs. 0.63±0.04, CD8 +: 0.82±0.06 vs. 0.70±0.04, both P < 0.05), indicating that the EZH2 inhibitor could increase the ratio of T lymphocytes with high proliferative activity in lymph nodes of septic mice. However, no significant difference was found on both CD4 + and CD8 + T lymphocytes apoptosis rates in the mesenteric lymph nodes of mice between CLP+GSK126 group and CLP+DMSO group [CD4 +: (21.53±2.87)% vs. (20.48±3.21)%, CD8 +: (8.34±1.02)% vs. (7.71±1.38)%, both P > 0.05], indicating that no extra T lymphocytes apoptosis was induced by EZH2 inhibitor. Compared with CLP+DMSO group, the ratios of IFN-γ + CD4 + and IFN-γ + CD8 + T lymphocytes were increased in CLP+GSK126 group (IFN-γ +CD4 +: 0.31±0.11 vs. 0.14±0.06, IFN-γ +CD8 +: 0.30±0.10 vs. 0.13±0.06, both P < 0.05), suggesting that secretion of IFN-γ in lymph nodes by sepsis T lymphocytes was augmented after EZH2 inhibitor administration. Furthermore, compared with CLP+DMSO group, the ratio of PD-1 + cell in CD8 + T lymphocyte was down-regulated in CLP+GSK126 group (0.092±0.006 vs. 0.135±0.004, P < 0.01), suggesting that EZH2 inhibitor restrained the PD-1 expression on sepsis lymphoid node CD8 + T lymphocytes, however, it had no significant effect on PD-L1 + cells. Conclusion:EZH2, regulates sepsis-induced T lymphocyte dysfunction, possibly through modulating the expression of PD-1.

Advances of inhibitors targeting MLL1-WDR5 protein-protein interaction / 中国药科大学学报

@#Mixed lineage leukemia 1(MLL1) is a member of the "SET" histone methyltransferases family.MLL1 methyltransferase complex, consisting of MLL1, WDR5, RbBP5, Ash2L and DPY-30, regulates methylation level of histone H3 lysine 4 and is essential for the development of human hematopoietic system and self-renewal of blood cells.As an oncogenic protein produced by the translocation of MLL1 gene, the MLL1 fusion protein has been found in some patients with leukemia.Complete MLL1 enzyme complex is required to perform histone demethylation effect, therefore, targeting the protein-protein interaction of MLL1-WDR5 has become a potential strategy for the treatment of leukemia induced by MLL1 fusion protein.This review systematically summarizes the biological mechanism, structural information and inhibitors of MLL1-WDR5 protein-protein interaction, with a perspective based on previously reported data, aiming to provide some reference for further investigation.

Suppressor of Variegation 3–9 Homolog 2, a Novel Binding Protein of Translationally Controlled Tumor Protein, Regulates Cancer Cell Proliferation

Suppressor of Variegation 3–9 Homolog 2 (SUV39H2) methylates the lysine 9 residue of histone H3 and induces heterochromatin formation, resulting in transcriptional repression or silencing of target genes. SUV39H1 and SUV39H2 have a role in embryonic development, and SUV39H1 was shown to suppress cell cycle progression associated with Rb. However, the function of human SUV39H2 has not been extensively studied. We observed that forced expression of SUV39H2 decreased cell proliferation by inducing G1 cell cycle arrest. In addition, SUV39H2 was degraded through the ubiquitin-proteasomal pathway. Using yeast two-hybrid screening to address the degradation mechanism and function of SUV39H2, we identified translationally controlled tumor protein (TCTP) as an SUV39H2-interacting molecule. Mapping of the interacting regions indicated that the N-terminal 60 amino acids (aa) of full-length SUV39H2 and the C-terminus of TCTP (120–172 aa) were critical for binding. The interaction of SUV39H2 and TCTP was further confirmed by co-immunoprecipitation and immunofluorescence staining for colocalization. Moreover, depletion of TCTP by RNAi led to up-regulation of SUV39H2 protein, while TCTP overexpression reduced SUV39H2 protein level. The half-life of SUV39H2 protein was significantly extended upon TCTP depletion. These results clearly indicate that TCTP negatively regulates the expression of SUV39H2 post-translationally. Furthermore, SUV39H2 induced apoptotic cell death in TCTP-knockdown cells. Taken together, we identified SUV39H2, as a novel target protein of TCTP and demonstrated that SUV39H2 regulates cell proliferation of lung cancer cells.

Effects of histone methyltransferase inhibitor on the polarization of peritoneal macrophages in septic mice / 中华危重病急救医学

Objective? To?investigate?the?effect?of?histone?methyltransferase?(EZH2)?inhibitor?on?the?polarization??of?peritoneal?macrophages?in?septic?mice.? Methods? Thirty-six?healthy?male?C57BL/6J?mice?were?divided?into?three?groups?by?random?number?table?method?(n?=?12):?sham?operated?group?(Sham?group),?sepsis?model?group?(CLP?group)??and?EZH2?inhibitor?treatment?group?(CLP+3-DZNeP?group).?Sepsis?animal?model?was?established?by?cecum?ligation?and?puncture?(CLP);?Sham?group?was?challenged?only?by?cecum?traction?without?ligation.?3-Deazaneplanocin?A?(3-DZNeP)?1?mg/kg?was?intraperitoneal?injected?24?hours?before?and?1?hour?after?CLP?in?CLP+3-DZNeP?group.?Eight?mice?in?each?group?were?sacrificed?at?24?hours?after?surgery.?The?levels?of?proinflammatory?cytokines?interleukin-6??(IL-6)?and?tumor?necrosis?factor-α(TNF-α)?in?peritoneal?lavatory?fluid?were?detected?by?high?throughput?liquid?protein?chip.?The?expression?levels?of?inducible?nitrogenase?(iNOS)?and?macrophage?mannose?receptor?(CD206)?were?analyzed?by?flow?cytometry.?Mouse?peritoneal?macrophages?were?isolated?and?purified?by?adherent?method,?the?protein?expressions?of?EZH2,?peroxisome?proliferator-activated?receptorγ(PPARγ)?were?detected?by?Western?Blot.?The?remaining?4?mice?? were?sacrificed?at?48?hours?after?surgery,?the?histopathological?changes?of?lung?and?kidney?tissue?were?evaluated?by?hematoxylin-eosin?(HE)?staining.? Results? Compared?with?Sham?group,?the?infiltration?of?inflammatory?cells?in?lung?and?kidney?of?the?CLP?group,?the?levels?of?IL-6?and?TNF-α?in?peritoneal?lavatory?fluid?were?significant?increased??[IL-6?(ng/L):?7?794.75±405.56?vs.?78.63±74.09,?TNF-α(ng/L):?147.25±25.19?vs.?18.20±5.03,?both?P?<?0.01],?the?percentage?of?M1?type?macrophages?was?significantly?increased?[iNOS+?F4/80+:?(13.18±8.80)%?vs.?(1.57±0.77)%,?P?<?0.05],?and?the?protein?expression?of?EZH2?was?significantly?increased?(EZH2/GAPDH:?0.84±0.11?vs.?0.11±0.03,?P?<?0.01),?while?the?protein?expression?of?PPARγ?was?significantly?decreased?(PPARγ/GAPDH:?0.09±0.01?vs.?0.27±0.09,?P?<?0.01).?Compared?with?CLP?group,?the?histopathological?changes?of?lung?and?kidney?in?CLP+3-DZNeP?group?were?significantly?alleviated,?the?levels?of?IL-6?and?TNF-α?in?peritoneal?lavatory?fluid?were?significantly?decreased?[IL-6?(ng/L):?4?207.10±876.60?vs.?7?794.75±405.56,?TNF-α(ng/L):?63.00±25.37?vs.?147.25±25.19,?both?P <?0.01?],?the?percentage?of?M1?type?macrophages?was?significantly?decreased?[iNOS+?F4/80+:?(3.64±0.89)%?vs.?(13.18±8.80)%,??P?<?0.05],?while?the?percentage?of?M2?type?macrophages?was?significantly?increased?[CD206+?F4/80+:?(17.68±5.63)%?vs.?(7.60±3.17)%,?P?<?0.01],?the?protein?expression?of?EZH2?was?significantly?decreased?(EZH2/GAPDH:?0.53±0.09?vs.?0.84±0.11,?P?<?0.05),?and?the?protein?expression?of?PPARγ?was?significantly?increased?(PPARγ/GAPDH:?0.39±0.14?vs.?0.09±0.01,?P?<?0.05).? Conclusions? Sepsis?induces?high?expression?of?EZH2?in?peritoneal?macrophages,?and?may?induce?polarization?of?M1?type?macrophages?by?inhibiting?the?expression?of?PPARγ?protein.?EZH2?inhibitor?3-DZNeP?can?lessen?the?inflammatory?cytokines?release?by?inhibiting?the?M1?type?macrophages?polarization.

Inhibition of G9a attenuates cell proliferation via the mitochondrial apoptosis pathway in lung adenocarcinoma / 中华肿瘤杂志

Objective@#The aim of this study is to investigate the effect of G9a inhibitor BIX-01294 on attenuating cell proliferation in human lung adenocarcinoma A549 cell line and the underlying molecular mechanism.@*Methods@#Treated with BIX-01294, the growth and proliferation of A549 cells were detected by MTT assay and colony formation assay, and its impact on cell apoptosis was analyzed using flow cytometry. By Western blot, we explored the alterations in the expression of apoptosis-related proteins and the G9a catalysate, H3K9me and H3K9me2. In addition, in the pretreatment with caspase inhibitor Z-VAD-FMK, we detected the apoptotic dependence of BIX-01294 attenuating impact on A549 cell proliferation.@*Results@#Compared with the control group, the histone methyltransferase G9a inhibitor BIX-01294 attenuated cell proliferation in A549 cells in a dose- and time-dependent manner. There were 42.5±8.7 colonies after BIX-01294 (10 μmol/L) treatment for 7 days, while 172.7±23.0 colonies in the control group, with a statistical significance (P<0.05). After treatment with BIX-01294 (10 μmol/L) for 24 hours, the cell apoptotic rate was(47.6±8.4)%, with a significant difference in comparison with the control group [(7.2±3.6)%, P<0.05]. The expression of G9a catalysate, H3K9me and H3K9me2 was downregulated, the same with anti-apoptotic protein Bcl-2, while the proteins in mitochondrial apoptosis pathway, Bax, Bak and cleaved caspase-9, were upregulated, so was the expression of cleaved caspase-3 and cleaved PARP, and there was no alteration in the expression of cleaved caspase-8, which is a protein related with death receptor apoptosis pathway. Furthermore, after Z-VAD-FMK pretreatment, the cell apoptotic rate was decreased significantly, and the expression of apoptosis-related proteins were downregulated.@*Conclusions@#Our results indicate that BIX-01294 can attenuate cell proliferation in lung adenocarcinoma, and it can be considered as one of the underlying mechanisms, the apoptosis may be induced by activating mitochondrial pathway.

DOT1L-long enhances breast cancer metastasis / 上海交通大学学报（医学版）

Objective · To investigate the histone methyltransferase capability of DOT1L-long form and its role in breast cancer metastasis.Methods · The existence of DOT1L-long form was confirmed by PCR, and the mRNA level of DOT1L was tested by real-time PCR. In HEK293T cells in which DOT1L canonical and DOT1L-long were overexpressed respectively, Western blotting was used to test the expression level of DOT1L and the histone methyltransferase capability. In the MCF10A cell line with inducible expression of DOT1L-long, real-time PCR was used to detect the mRNA level of epithelial-mesenchymal transition (EMT) marker, and transwell assay was used to detect the migration of breast cancer cells in which the expression level of DOT1L is low or high. Results · PCR demonstrated the existence of DOT1L-long form, and real-time PCR showed it widely exists in HCT116, T98G, MCF10A cells, etc. Western blotting showed the expression of DOT1L-long form and its H3K79 methyltransferase activity. In MCF10A cells in which overexpressed canonical DOT1L and DOT1L-long, mRNA levels of N-cadherin and fibronectine increased. Transwell showed canonical DOT1L and DOT1L-long both substantially increased the migration of breast cancer cells. Conclusion · The existence of DOT1L-long was confirmed and investigated, which is 202 amino acids longer than the canonical DOT1L, and is coded by a new exon, located between exon 27 and 28. Further, the DOT1L-long has H3K79 methyltransferase activity, and is able to promote breast cancer metastasis.

DOT1L-long enhances breast cancer metastasis / 上海交通大学学报（医学版）

Objective · To investigate the histone methyltransferase capability of DOT1L-long form and its role in breast cancer metastasis.Methods · The existence of DOT1L-long form was confirmed by PCR, and the mRNA level of DOT1L was tested by real-time PCR. In HEK293T cells in which DOT1L canonical and DOT1L-long were overexpressed respectively, Western blotting was used to test the expression level of DOT1L and the histone methyltransferase capability. In the MCF10A cell line with inducible expression of DOT1L-long, real-time PCR was used to detect the mRNA level of epithelial-mesenchymal transition (EMT) marker, and transwell assay was used to detect the migration of breast cancer cells in which the expression level of DOT1L is low or high. Results · PCR demonstrated the existence of DOT1L-long form, and real-time PCR showed it widely exists in HCT116, T98G, MCF10A cells, etc. Western blotting showed the expression of DOT1L-long form and its H3K79 methyltransferase activity. In MCF10A cells in which overexpressed canonical DOT1L and DOT1L-long, mRNA levels of N-cadherin and fibronectine increased. Transwell showed canonical DOT1L and DOT1L-long both substantially increased the migration of breast cancer cells. Conclusion · The existence of DOT1L-long was confirmed and investigated, which is 202 amino acids longer than the canonical DOT1L, and is coded by a new exon, located between exon 27 and 28. Further, the DOT1L-long has H3K79 methyltransferase activity, and is able to promote breast cancer metastasis.

Advances of SMYD3 in hepatic carcinoma / 国际外科学杂志

Histone methyltransferase SMYD3 (SET and MYND domain containing 3) is a protein which has the function of histone methylation found in recent years,it has an important role in transcriptional regulation.The research shows that SMYD3 inhibit apoptosis and promote cell proliferation,invasion and metastasis.More and more data shows SMYD3 highly expressed in liver cancer and is low in normal tissues which is even undetectable.SMYD3 level was significantly associated with prognosis,and gene silencing experiments in SMYD3 tumor cell growth was inhibited.Therefor,SMYD3 is closely related with the development and prognosis of HCC occurrence,which suggests that people can suppress the expression SMYD3 to block tumor cell growth,migration and improve prognosis to provide new goals and direction for the future of cancer treatment.

Research progress of epigenetic regulation of histone methyltransferase EZH2 in hematologic neoplasms / 白血病·淋巴瘤

The histone H3 lysine 27 methyltransferase EZH2 takes part in heterochromatin formation and gene transcription regulation.EZH2 is frequently over-expressed in a wide variety of cancerous tissue types,which reveals it to be oncogenic.However,in myeloid malignancies,EZH2 could act as a tumor suppressor.This paper mainly reviews the structure and function of EZH2 and its effect on hematologic neoplasms.Taking EZH2 as target will provide systematic understanding for the treatment of hematologic neoplasms.

Improved Therapeutic Effect against Leukemia by a Combination of the Histone Methyltransferase Inhibitor Chaetocin and the Histone Deacetylase Inhibitor Trichostatin A

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.

Epigenetic Cross-Talk between DNA Methylation and Histone Modifications in Human Cancers

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.

Epigenetic Cross-Talk between DNA Methylation and Histone Modifications in Human Cancers

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.

Advance in The Studies on Histone Methylation / 生物化学与生物物理进展

Histone methylation is one of the epigenetic modifications. Histone methylation influences constitutive heterochromatin, genomic imprinting, inactivation of X-chromosome and gene transcription regulation. Abnormality of histone methylation is associated with several carcinomas. The discovery of enzymes that reverse histone methylation challenges the current understanding that histone methylation is a stable epigenetic marker and provides a novel way to study histone modifications.