Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cel...Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cell cycle. Immortalized mouse hippocampal neuronal precursor cells(HT_(22)) were treated with 0.3 or 3 μM BpV. Proliferation, morphology, and viability of HT_(22) cells were detected with an IncuCyte real-time video imaging system or inverted microscope and 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, respectively. mRNA and protein expression of DNMTs and p21 in HT_(22) cells was detected by real-time polymerase chain reaction and immunoblotting, respectively. In addition, DNMT activity was measured with an enzyme-linked immunosorbent assay. Effects of BpV on the cell cycle were analyzed using flow cytometry. Results demonstrated that treatment with 0.3 μM BpV did not affect cell proliferation, morphology, or viability; however, treatment with 3 μM BpV decreased cell viability, increased expression of both DNMT3B mRNA and protein, and inhibited the proliferation of HT_(22) cells; and 3 μM BpV also blocked the cell cycle and increased expression of the regulatory factor p21 by increasing DNMT expression in mouse hippocampal neurons.展开更多
The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nerv...The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases (DNMTs), mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.展开更多
DNA methylation is an important epigenetic regulation mechanism, which is catalyzed by DNA methyltransferases. In this study, eight DNA methyltransferase genes were identified in grape genome to analyze the selective ...DNA methylation is an important epigenetic regulation mechanism, which is catalyzed by DNA methyltransferases. In this study, eight DNA methyltransferase genes were identified in grape genome to analyze the selective pressure, gene expression and codon usage bias. The results showed grape DNA methyltransferase MET subfamily underwent relatively strong purifying selection during evolution, while chromomethylase CMT subfamily underwent positive selection during evolution. Under different abiotic(heat, drought or cold) stresses, the expression level of many grape DNA methyltransferase genes changed significantly. The expression level of these genes might be related with cis-regulatory elements of their promoters. The results of codon usage bias analysis showed that synonymous codon bias existed in grape DNA methyltransferase gene family, which might be affected by mutation pressure. These results laid a solid foundation for in-depth study of DNA methyltransferases in grape.展开更多
DNA methyltransferases 1 (DNMT1) has been looked as crucial targets against various types of cancers. MD simulations have advanced to a point where the atomic level information of biological macromolecule (protein or ...DNA methyltransferases 1 (DNMT1) has been looked as crucial targets against various types of cancers. MD simulations have advanced to a point where the atomic level information of biological macromolecule (protein or DNA-protein or protein-protein) can easily be advantageous to predict the functionality. In this study we utilize xanthomicrol and galloyl compounds to investigate potential compounds for the inhibition of DNMT1, and the results of these two compounds are compared with drug decitabine. Xanthomicrol and galloyl are found to dock successfully within the active site of DNMT1. A comparison of the inhibitory potential of screened xanthomicrol inhibited DNMT1 approximately is identical with those of their corresponding drugs, decitabine. The stability of the DNMT1 with the best docked xanthomicrol, were further analysed in molecular dynamics (MD) simulation and compared with those of the respective drugs namely decitabine which revealed stabilization of these complexes within 300 ns of simulation with better stability of DNMT1.展开更多
Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder...Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder Wolf Hirschhorn syndrome (WHS), which is characterized by growth and mental retardation, congenital heart defects, etc. Moreover, it is over-expressed in a large number of tumors, including malignant melanoma. However, the underlying mechanisms of its deregulation in most tumors are still not unclear.展开更多
Objective: To investigate the mRNA and protein expression of histone methyltransferase G9a and its clinical significance in extrahepatic cholangiocarcinoma. Methods: Using RT-PCR and Western Blotting to detect the exp...Objective: To investigate the mRNA and protein expression of histone methyltransferase G9a and its clinical significance in extrahepatic cholangiocarcinoma. Methods: Using RT-PCR and Western Blotting to detect the expression of G9a at the level of mRNA and protein in 48 tumor samples and 39 control tissues. Results: The mRNA and protein expres- sion of G9a in extrahepatic cholangiocarcinoma was higher than control statistically (P < 0.05) and positively correlated with lymph metastasis (P < 0.05) and TNM stage (P < 0.01). Conclusion: The significant difference of G9a expression between tumors and control implicated that the important role of histone methylation disruption resulted from increased G9a expression in extrahepatic cholangiocarcinoma.展开更多
The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chem...The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.展开更多
DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that...DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that have functional methylation activities,termed DNMT1,DNMT3A,and DNMT3B.DNMT3A and DNMT3B are responsible for methylation establishment,whereas DNMT1 maintains methylation during DNA replication.Accumulating evidence demonstrates that regulation of DNAmethylation by DNMTs is critical for normal hematopoiesis.Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies,such as DNMT3A mutations in acute myeloid leukemia.In this reviewwe first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation,We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets.We also discuss DNMT mu-tations and pathogenic roles in human leukemia and lymphoma.We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes.Firnally.we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.展开更多
Mesenchymal stem cells (MSCs) are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-ba...Mesenchymal stem cells (MSCs) are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing family and the Jumonji C (JmjC) domain-containing family represent the major histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.展开更多
Non-alcoholic fatty liver disease(NAFLD)poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits.Its complexity stems from genetic predisposition,environmental influences,...Non-alcoholic fatty liver disease(NAFLD)poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits.Its complexity stems from genetic predisposition,environmental influences,and metabolic factors.Epigenetic processes govern various cellular functions such as transcription,chromatin structure,and cell division.In NAFLD,these epigenetic tendencies,especially the process of histone methylation,are intricately intertwined with fat accumulation in the liver.Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis.While early-stage NAFLD is reversible,its progression to severe stages becomes almost irreversible.Therefore,early detection and intervention in NAFLD are crucial,and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.展开更多
This paper investigated the age-related changes in the expression patterns of maintenance methyltransferase (DNMT1) and de novo methyltransferases (DNMT3a, 3b, 3L) and the chromosome architecture in in-vivo matured mo...This paper investigated the age-related changes in the expression patterns of maintenance methyltransferase (DNMT1) and de novo methyltransferases (DNMT3a, 3b, 3L) and the chromosome architecture in in-vivo matured mouse oocytes using two-photon laser-scanning microscope. Our results showed that (1) DNMT1 and DNMT3a, 3b, 3L in the oocytes of pubertal mice were located in the cortical region of oocyte cytoplasm. In aging groups, DNMT1 was also located in the cortical region. However, DNMT3a, 3b, 3L had a relatively wider distribution in the oocyte cytoplasm and appeared near the chromosomes. These differences between pubertal and aging groups suggested that aging might affect DNA methylation; (2) the expression of DNMT1, and DNMT3a, 3b in aging groups increased significantly compared to pubertal groups, while, the expression of DNMT3L decreased. These results might be explained by the compensation mechanism among DNMTs, which might be impervious to aging; (3) aging caused increased errors in the distribution and three-dimensional morphology of chromosomes, including the increased total volume and surface area, the high ratio of height to diameter of a circular cylinder enclosing the chromosomes (H/D). Our work provided morphological information for the studies of age-related decline in oocyte qualities.展开更多
Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A lar...Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A large number of SET-domain genes are identified in plant genomes. The function of most SET-domain genes is not known. In this work, we studied the 12 rice (Oryza sativa) homologs of Su(var)3-9, the histone H3 lysine 9 (H3K9) methyltransferase identified in Drosophila. Several rice SUVHs (i.e. SDG714, SDG727, and SDG710) were found to have an antagonistic func- tion to the histone H3K9 demethylase JMJ706, as down-regulation of these genes could partially complement the jmj706 phenotype and reduced histone H3K9 methylation. Down-regulation of a rice Su(var)3-9 homolog (SUVH), namely SDG728, decreased H3K9 methylation and altered seed morphology. Overexpression of the gene increased H3K9 methylation. SDG728 and other SUVH genes were found to be involved in the repression of retrotransposons such as Tos17 and a Tyl-copia element. Analysis of histone methylation suggested that SDG728-mediated H3K9 methylation may play an important role in retrotransposon repression.展开更多
High rate of abortion and developmental abnormalities is thought to be closely associated with inefficient epigenetic reprogramming of the transplanted nuclei during bovine cloning. It is known that one of the importa...High rate of abortion and developmental abnormalities is thought to be closely associated with inefficient epigenetic reprogramming of the transplanted nuclei during bovine cloning. It is known that one of the important mechanisms for epigenetic reprogramming is DNA methylation. DNA methylation is established and maintained by DNA methyltransferases (DNMTs), therefore, it is postulated that the inefficient epigenetic reprogramming of transplanted nuclei may be due to abnormal expression of DNMTs. Since DNA methylation can strongly inhibit gene expression, aberrant DNA methylation of DNMT genes may disturb gene expression. But presently, it is not clear whether the methylation abnormality of DNMT genes is related to developmental failure of somatic cell nuclear transfer embryos. In our study, we analyzed methylation patterns of the 5' regions of four DNMT genes including Dnmt3a, Dnmt3b, Dnmtl and Dnmt2 in four aborted bovine clones. Using bisulfite sequencing method, we found that 3 out of 4 aborted bovine clones (AF1, AF2 and AF3) showed either hypermethylation or hypomethylation in the 5' regions of Dnmt3a and Dnmt3b, indicating that Dnmt3a and Dnmt3b genes are not properly reprogrammed. However, the individual AF4 exhibited similar methylation level and pattern to age-matched in vitro fertilized (IVF) fetuses. Besides, we found that the 5' regions of Dnmtl and Dnmt2 were nearly completely unmethylated in all normal adults, IVF fetuses, sperm and aborted clones. Together, our results suggest that the aberrant methylation of Dnmt3a and Dnmt3b 5' regions is probably associated with the high abortion of bovine clones.展开更多
AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value.METHODS: From April 2000 to December 2010, 227men and 73 women with gastric cancer were enrolled ...AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value.METHODS: From April 2000 to December 2010, 227men and 73 women with gastric cancer were enrolled in the study. The expression of DNA methyltransferases(DNMTs), including DNMT1, DNMT3a and DNMT3b,in the 300 cases of gastric carcinoma, of which 85 hadpaired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray. Serum anti-Helicobacter pylori(H. pylori) IgG was detected by enzyme-linked immunosorbent assay(ELISA). The relationships between the above results and the clinicopathological characteristics were analyzed. Their prognostic value was evaluated using the Cox proportional hazards model.RESULTS: In gastric cancer, expression of DNMTs was mainly seen in the nucleus. Weak staining was also observed in the cytoplasm. Expression of DNMT1, DNMT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples(60.0% vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01). The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients(Log-rank test, P = 0.032). No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time(Log-rank test, P = 0.289, P = 0.347). Multivariate regression analysis indicated that DNMT3a expression(P = 0.025) and TNM stage(P < 0.001), but not DNMT1(P = 0.54) or DNMT3b(P = 0.62), were independent prognostic factors in gastric cancer. H. pylori infection did not induce protein expression of DNMTs.CONCLUSION: The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer. DNMT3a might play an important role in gastric carcinogenesis.展开更多
基金supported by the National Natural Science Foundation of China,No.81160244,81360316,81460283,81660307(all to GS)the Inner Mongolia Science Foundation of China,No.2018LH08078(to GS),2016MS(LH)0307(to SYJ)+4 种基金the Baotou Health Foundation,China,No.WSJJ2016008(to SYJ)the Inner Mongolia Educational Research Foundation of China,No.NJZY207(to GS),NJZY17243(to SCY),NJZY17250(to XLL),NJZY17251(to SYJ)the Baotou Medical College Foundation of China,No.BYJJ-DF201602,BYJJ-YF201615,BSJJ201617,BYJJ-QM201633,BYJJ-QM201656,BYJJ201502(to GS)the Science and Technology Planning Project of Baotou of China,No.CX2017-5(to GS)the National Key R&D Program of China,No.2017YFC1308405(to GS)
文摘Bisperoxo(1,10-phenanthroline) oxovanadate(BpV) can reportedly block the cell cycle. The present study examined whether BpV alters gene expression by affecting DNA methyltransferases(DNMTs), which would impact the cell cycle. Immortalized mouse hippocampal neuronal precursor cells(HT_(22)) were treated with 0.3 or 3 μM BpV. Proliferation, morphology, and viability of HT_(22) cells were detected with an IncuCyte real-time video imaging system or inverted microscope and 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, respectively. mRNA and protein expression of DNMTs and p21 in HT_(22) cells was detected by real-time polymerase chain reaction and immunoblotting, respectively. In addition, DNMT activity was measured with an enzyme-linked immunosorbent assay. Effects of BpV on the cell cycle were analyzed using flow cytometry. Results demonstrated that treatment with 0.3 μM BpV did not affect cell proliferation, morphology, or viability; however, treatment with 3 μM BpV decreased cell viability, increased expression of both DNMT3B mRNA and protein, and inhibited the proliferation of HT_(22) cells; and 3 μM BpV also blocked the cell cycle and increased expression of the regulatory factor p21 by increasing DNMT expression in mouse hippocampal neurons.
文摘The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases (DNMTs), mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.
基金Supported by Major Agricultural Application Technology Innovation Project of Shandong Province"Research and Application of Precision Control of Maturation and Product Innovation of Featured Brewing Grape"Major Agricultural Application Technology Innovation Project of Shandong Province"Development of Landmark Wines and Integrated Application of Key Technologies in Shandong Province"Agricultural Scientific and Technological Innovation Project of Shandong Academy of Agricultural Sciences(CXGC2016D01)
文摘DNA methylation is an important epigenetic regulation mechanism, which is catalyzed by DNA methyltransferases. In this study, eight DNA methyltransferase genes were identified in grape genome to analyze the selective pressure, gene expression and codon usage bias. The results showed grape DNA methyltransferase MET subfamily underwent relatively strong purifying selection during evolution, while chromomethylase CMT subfamily underwent positive selection during evolution. Under different abiotic(heat, drought or cold) stresses, the expression level of many grape DNA methyltransferase genes changed significantly. The expression level of these genes might be related with cis-regulatory elements of their promoters. The results of codon usage bias analysis showed that synonymous codon bias existed in grape DNA methyltransferase gene family, which might be affected by mutation pressure. These results laid a solid foundation for in-depth study of DNA methyltransferases in grape.
文摘DNA methyltransferases 1 (DNMT1) has been looked as crucial targets against various types of cancers. MD simulations have advanced to a point where the atomic level information of biological macromolecule (protein or DNA-protein or protein-protein) can easily be advantageous to predict the functionality. In this study we utilize xanthomicrol and galloyl compounds to investigate potential compounds for the inhibition of DNMT1, and the results of these two compounds are compared with drug decitabine. Xanthomicrol and galloyl are found to dock successfully within the active site of DNMT1. A comparison of the inhibitory potential of screened xanthomicrol inhibited DNMT1 approximately is identical with those of their corresponding drugs, decitabine. The stability of the DNMT1 with the best docked xanthomicrol, were further analysed in molecular dynamics (MD) simulation and compared with those of the respective drugs namely decitabine which revealed stabilization of these complexes within 300 ns of simulation with better stability of DNMT1.
文摘Nuclear Receptor-binding SET Domain 2 (NSD2) is a SET domain-containing protein lysine methyltransferase (PKMT) implicated in a lot of human diseases. Its haploinsufficiency is implicated in the developmental disorder Wolf Hirschhorn syndrome (WHS), which is characterized by growth and mental retardation, congenital heart defects, etc. Moreover, it is over-expressed in a large number of tumors, including malignant melanoma. However, the underlying mechanisms of its deregulation in most tumors are still not unclear.
基金Supported by a grant from the National High Technology ResearchDevelopment Program of China (863 Program) (No. 2002AA214061)
文摘Objective: To investigate the mRNA and protein expression of histone methyltransferase G9a and its clinical significance in extrahepatic cholangiocarcinoma. Methods: Using RT-PCR and Western Blotting to detect the expression of G9a at the level of mRNA and protein in 48 tumor samples and 39 control tissues. Results: The mRNA and protein expres- sion of G9a in extrahepatic cholangiocarcinoma was higher than control statistically (P < 0.05) and positively correlated with lymph metastasis (P < 0.05) and TNM stage (P < 0.01). Conclusion: The significant difference of G9a expression between tumors and control implicated that the important role of histone methylation disruption resulted from increased G9a expression in extrahepatic cholangiocarcinoma.
基金the Science and Technology Commission of Shanghai,China(Grant Nos.:20DZ2270800 and 19JC1410200)Innovative Research Team of High-Level Local Universities in Shanghai,China(Grant No.:SHSMU-ZDCX20210900)the National Natural Science Foundation of China(Grant No.:82073889).
文摘The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
基金the National lnstitutes of Health/National Cancer Institute(NlH/NCT)grant RO1 CA187299(L.R.)。
文摘DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that have functional methylation activities,termed DNMT1,DNMT3A,and DNMT3B.DNMT3A and DNMT3B are responsible for methylation establishment,whereas DNMT1 maintains methylation during DNA replication.Accumulating evidence demonstrates that regulation of DNAmethylation by DNMTs is critical for normal hematopoiesis.Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies,such as DNMT3A mutations in acute myeloid leukemia.In this reviewwe first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation,We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets.We also discuss DNMT mu-tations and pathogenic roles in human leukemia and lymphoma.We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes.Firnally.we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.
基金supported by the National Institute of Dental and Craniofacial Research grants, K08DE024603-02, DE019412, and DE01651a grant from 111 Project of MOE, Chinasupported by Open Fund of State Key Laboratory of Oral Diseases, Sichuan University
文摘Mesenchymal stem cells (MSCs) are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing family and the Jumonji C (JmjC) domain-containing family represent the major histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containine KMTs and JmiC domain-containinlz KDMs balance the osteogenic and adipogenic differentiation of MSCs.
文摘Non-alcoholic fatty liver disease(NAFLD)poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits.Its complexity stems from genetic predisposition,environmental influences,and metabolic factors.Epigenetic processes govern various cellular functions such as transcription,chromatin structure,and cell division.In NAFLD,these epigenetic tendencies,especially the process of histone methylation,are intricately intertwined with fat accumulation in the liver.Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis.While early-stage NAFLD is reversible,its progression to severe stages becomes almost irreversible.Therefore,early detection and intervention in NAFLD are crucial,and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.
基金supported by the National Natural Science Foundation of China (90919012 and 10874099)National Basic Research Program of China (2007CB5119004)+1 种基金the Doctoral Program Research Fund of the Chinese Ministry of Education (20090002110065)the Tsinghua University Initiative Scientific Research Program (2010THZ01)
文摘This paper investigated the age-related changes in the expression patterns of maintenance methyltransferase (DNMT1) and de novo methyltransferases (DNMT3a, 3b, 3L) and the chromosome architecture in in-vivo matured mouse oocytes using two-photon laser-scanning microscope. Our results showed that (1) DNMT1 and DNMT3a, 3b, 3L in the oocytes of pubertal mice were located in the cortical region of oocyte cytoplasm. In aging groups, DNMT1 was also located in the cortical region. However, DNMT3a, 3b, 3L had a relatively wider distribution in the oocyte cytoplasm and appeared near the chromosomes. These differences between pubertal and aging groups suggested that aging might affect DNA methylation; (2) the expression of DNMT1, and DNMT3a, 3b in aging groups increased significantly compared to pubertal groups, while, the expression of DNMT3L decreased. These results might be explained by the compensation mechanism among DNMTs, which might be impervious to aging; (3) aging caused increased errors in the distribution and three-dimensional morphology of chromosomes, including the increased total volume and surface area, the high ratio of height to diameter of a circular cylinder enclosing the chromosomes (H/D). Our work provided morphological information for the studies of age-related decline in oocyte qualities.
文摘Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A large number of SET-domain genes are identified in plant genomes. The function of most SET-domain genes is not known. In this work, we studied the 12 rice (Oryza sativa) homologs of Su(var)3-9, the histone H3 lysine 9 (H3K9) methyltransferase identified in Drosophila. Several rice SUVHs (i.e. SDG714, SDG727, and SDG710) were found to have an antagonistic func- tion to the histone H3K9 demethylase JMJ706, as down-regulation of these genes could partially complement the jmj706 phenotype and reduced histone H3K9 methylation. Down-regulation of a rice Su(var)3-9 homolog (SUVH), namely SDG728, decreased H3K9 methylation and altered seed morphology. Overexpression of the gene increased H3K9 methylation. SDG728 and other SUVH genes were found to be involved in the repression of retrotransposons such as Tos17 and a Tyl-copia element. Analysis of histone methylation suggested that SDG728-mediated H3K9 methylation may play an important role in retrotransposon repression.
基金the National Basic Re-search Program of China (973 Program) (No. 2006CB504004 and 2006CB944004)the National Natural Science Foundation of China (No. 30430530)the Knowledge Innovation Program of the Chinese Academy of Sciences (No. KSCX2-YW-N-017).
文摘High rate of abortion and developmental abnormalities is thought to be closely associated with inefficient epigenetic reprogramming of the transplanted nuclei during bovine cloning. It is known that one of the important mechanisms for epigenetic reprogramming is DNA methylation. DNA methylation is established and maintained by DNA methyltransferases (DNMTs), therefore, it is postulated that the inefficient epigenetic reprogramming of transplanted nuclei may be due to abnormal expression of DNMTs. Since DNA methylation can strongly inhibit gene expression, aberrant DNA methylation of DNMT genes may disturb gene expression. But presently, it is not clear whether the methylation abnormality of DNMT genes is related to developmental failure of somatic cell nuclear transfer embryos. In our study, we analyzed methylation patterns of the 5' regions of four DNMT genes including Dnmt3a, Dnmt3b, Dnmtl and Dnmt2 in four aborted bovine clones. Using bisulfite sequencing method, we found that 3 out of 4 aborted bovine clones (AF1, AF2 and AF3) showed either hypermethylation or hypomethylation in the 5' regions of Dnmt3a and Dnmt3b, indicating that Dnmt3a and Dnmt3b genes are not properly reprogrammed. However, the individual AF4 exhibited similar methylation level and pattern to age-matched in vitro fertilized (IVF) fetuses. Besides, we found that the 5' regions of Dnmtl and Dnmt2 were nearly completely unmethylated in all normal adults, IVF fetuses, sperm and aborted clones. Together, our results suggest that the aberrant methylation of Dnmt3a and Dnmt3b 5' regions is probably associated with the high abortion of bovine clones.
基金Supported by Norman Bethune Program of Jilin University,No.2013025National Natural Science Foundation of China,No.81072369 and No.81273065
文摘AIM: To explore the alteration of DNA methyltransferase expression in gastric cancer and to assess its prognostic value.METHODS: From April 2000 to December 2010, 227men and 73 women with gastric cancer were enrolled in the study. The expression of DNA methyltransferases(DNMTs), including DNMT1, DNMT3a and DNMT3b,in the 300 cases of gastric carcinoma, of which 85 hadpaired adjacent normal gastric mucus samples, was evaluated by immunohistochemistry using a tissue microarray. Serum anti-Helicobacter pylori(H. pylori) IgG was detected by enzyme-linked immunosorbent assay(ELISA). The relationships between the above results and the clinicopathological characteristics were analyzed. Their prognostic value was evaluated using the Cox proportional hazards model.RESULTS: In gastric cancer, expression of DNMTs was mainly seen in the nucleus. Weak staining was also observed in the cytoplasm. Expression of DNMT1, DNMT3a and DNMT3b in gastric cancer was significantly higher compared to that in the paired control samples(60.0% vs 37.6%, 61.2% vs 4.7%, and 94.1% vs 71.8%, P < 0.01). The overall survival rate was significantly higher in the DNMT3a negative group than in the DNMT3a positive group in gastric cancer patients(Log-rank test, P = 0.032). No significant correlation was observed between DNMT1 and DNMT3b expression and the overall survival time(Log-rank test, P = 0.289, P = 0.347). Multivariate regression analysis indicated that DNMT3a expression(P = 0.025) and TNM stage(P < 0.001), but not DNMT1(P = 0.54) or DNMT3b(P = 0.62), were independent prognostic factors in gastric cancer. H. pylori infection did not induce protein expression of DNMTs.CONCLUSION: The results suggest that expression of DNMT3a is an independent poor prognostic indicator in gastric cancer. DNMT3a might play an important role in gastric carcinogenesis.