[Objective] This study aimed to conduct bioinformatics analysis of histone H3-1ys-4 （H3K4） methyltransferase MLL3 in animals, thus exploring its relatively conservative evolution to reveal the role of histon H3K4 tr...[Objective] This study aimed to conduct bioinformatics analysis of histone H3-1ys-4 （H3K4） methyltransferase MLL3 in animals, thus exploring its relatively conservative evolution to reveal the role of histon H3K4 trimethyltransferase MLL3 in human cancers. [Method] By using bioinformatics method, gene structure, amino acid sequences, phylogenetic tree, chromosomal localization and synteny of mouse MLL3 were analyzed. [Result] Primary structure of the encoded mouse MLL3 protein con- tained seven zinc finger domains, an HMG-box （High mobility group-box protein）, a FYRN （F/Y-rich N-terminus） domain, a FYRC （F/Yrich C-terminus） domain, a SET domain and a postSET domain. Results of sequence comparison and homology showed that 19 animal species in this study all had these structures basically, which indicated that these structures were relatively conserved in the evolution; specifically, the SET domain was highly conserved and was necessary to maintain the activity of histone methyltransferases. Results of phylogenetic analysis showed that the loca- tions of the 19 animal species in evolutionary tree were consistent with the taxo- nomic status. Results of synteny analysis showed that there were the same gene in the upstream and downstream of the mouse and human MLL3 gene which were located on different chromosomes, indicating that the mouse and human MLL3 gene had collinearity. [Conclusion] This study had revealed the primary structure of MLL3 nucleotide sequence and amino acid sequence, which had not only laid the foundation for the future research of high-level structure and function of MLL3 protein but also provided the basis for the follow-up study of primer design, promoter analysis, gene cloning and regulation patterns of localization and expression of mouse MLL3 gene.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
SETDB1 has been established as an oncogene in a number of human carcinomas. The present study was to evaluate the expression of SETDB1 in prostate cancer （PCa） tissues and cells and to preliminarily investigate the ...SETDB1 has been established as an oncogene in a number of human carcinomas. The present study was to evaluate the expression of SETDB1 in prostate cancer （PCa） tissues and cells and to preliminarily investigate the role of SETDB1 in prostate tumorigenesis in vitro. Quantitative reverse transcription polymerase chain reaction （qRT-PCR） and immunohistochemistry （IHC） were used to detect the expression of SETDB1 in PCa tissues, adjacent normal tissues, benign prostatic hyperplasia （BPH） tissues, PCa cell lines and normal prostate epithelial cells. The results suggested that SETDB1 was upregulated in human PCa tissues compared with normal tissues at the mRNA and protein levels. The role of SETDB1 in proliferation was analyzed with cell counting kit-8, colony-forming efficiency and flow cytometry assays. The results indicated that downregulation of SETDB1 by siRNA inhibited PCa cell growth, and induced GO/G1 cell cycle arrest. The PCa cell migration and invasion decreased by silcencing SETDBt which were assessed by using in vitro scratch and transwell invasion assay respectively. Our data suggested that SETDB1 is overexpressed in human PCa. Silencing SETDB1 inhibited PCa cell proliferation, migration and invasion.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
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 e...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 expression of Gga 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 Gga 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
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 effects of DNA methylation and histone deacetylase inhibitors in the re-expression of P16 and RASSIF1A of QBC939. Methods: The QBC939 cells were treated with hydralazine and valproate eit...Objective: To investigate the effects of DNA methylation and histone deacetylase inhibitors in the re-expression of P16 and RASSIF1A of QBC939. Methods: The QBC939 cells were treated with hydralazine and valproate either alone or combined, and the control group was added with RPIM-1640 culture medium. After 48 h, the expression of P16 and RASSF1A genes were evaluated by reverse transcription-PCR, Western blot, and the methylation status of the two genes were detected with MSP (methylation specific PCR). Results: Hydralazine and valproate could induce demethylation of the promoter region of the two genes, and could make them re-active. The expressions of P16 and RASSF1A of cells treated with both drugs were higher than that of the cells treated with either hydralazine or valproate (P < 0.01). There was no RASSF1A gene, and few P16 gene expressing in the control group. The demethylation effect could be found in the groups treated with hydralazine or both drugs, whereas no demethylation effect happened in the valproate group. Conclusion: The two drugs could synergistically re-express P16 and RASSF1A genes silenced in QBC939, and they exerted a great anti-tumour effect on QBC cells.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
基金Supported by National Natural Science Foundation of China (No.31071310)Provincial Scientific Research Institution Commissioned Special Project of Fuyang Normal University (No.2011PTFY03ZD)+1 种基金Natural Science Research Project for Universities from the Education Department of Anhui Province (KJ2011B121)Natural Science Foundation of Fuyang Normal University (No.2010FSKJ13)~~
文摘[Objective] This study aimed to conduct bioinformatics analysis of histone H3-1ys-4 （H3K4） methyltransferase MLL3 in animals, thus exploring its relatively conservative evolution to reveal the role of histon H3K4 trimethyltransferase MLL3 in human cancers. [Method] By using bioinformatics method, gene structure, amino acid sequences, phylogenetic tree, chromosomal localization and synteny of mouse MLL3 were analyzed. [Result] Primary structure of the encoded mouse MLL3 protein con- tained seven zinc finger domains, an HMG-box （High mobility group-box protein）, a FYRN （F/Y-rich N-terminus） domain, a FYRC （F/Yrich C-terminus） domain, a SET domain and a postSET domain. Results of sequence comparison and homology showed that 19 animal species in this study all had these structures basically, which indicated that these structures were relatively conserved in the evolution; specifically, the SET domain was highly conserved and was necessary to maintain the activity of histone methyltransferases. Results of phylogenetic analysis showed that the loca- tions of the 19 animal species in evolutionary tree were consistent with the taxo- nomic status. Results of synteny analysis showed that there were the same gene in the upstream and downstream of the mouse and human MLL3 gene which were located on different chromosomes, indicating that the mouse and human MLL3 gene had collinearity. [Conclusion] This study had revealed the primary structure of MLL3 nucleotide sequence and amino acid sequence, which had not only laid the foundation for the future research of high-level structure and function of MLL3 protein but also provided the basis for the follow-up study of primer design, promoter analysis, gene cloning and regulation patterns of localization and expression of mouse MLL3 gene.
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.
基金This study was supported by the National Basic Research Program of China （No. 2012CB518306）, the National Natural Science Foundation of China （No. 81101946）, the Prostate Cancer Foundation Young Investigator Award and the Shanghai Pujiang Program （No. 12PID008）.
文摘SETDB1 has been established as an oncogene in a number of human carcinomas. The present study was to evaluate the expression of SETDB1 in prostate cancer （PCa） tissues and cells and to preliminarily investigate the role of SETDB1 in prostate tumorigenesis in vitro. Quantitative reverse transcription polymerase chain reaction （qRT-PCR） and immunohistochemistry （IHC） were used to detect the expression of SETDB1 in PCa tissues, adjacent normal tissues, benign prostatic hyperplasia （BPH） tissues, PCa cell lines and normal prostate epithelial cells. The results suggested that SETDB1 was upregulated in human PCa tissues compared with normal tissues at the mRNA and protein levels. The role of SETDB1 in proliferation was analyzed with cell counting kit-8, colony-forming efficiency and flow cytometry assays. The results indicated that downregulation of SETDB1 by siRNA inhibited PCa cell growth, and induced GO/G1 cell cycle arrest. The PCa cell migration and invasion decreased by silcencing SETDBt which were assessed by using in vitro scratch and transwell invasion assay respectively. Our data suggested that SETDB1 is overexpressed in human PCa. Silencing SETDB1 inhibited PCa cell proliferation, migration and invasion.
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 expression of Gga 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 Gga expression between tumors and control implicated that the important role of histone methylation disruption resulted from increased G9a expression in extrahepatic cholangiocarcinoma.
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.
文摘Objective: To investigate the effects of DNA methylation and histone deacetylase inhibitors in the re-expression of P16 and RASSIF1A of QBC939. Methods: The QBC939 cells were treated with hydralazine and valproate either alone or combined, and the control group was added with RPIM-1640 culture medium. After 48 h, the expression of P16 and RASSF1A genes were evaluated by reverse transcription-PCR, Western blot, and the methylation status of the two genes were detected with MSP (methylation specific PCR). Results: Hydralazine and valproate could induce demethylation of the promoter region of the two genes, and could make them re-active. The expressions of P16 and RASSF1A of cells treated with both drugs were higher than that of the cells treated with either hydralazine or valproate (P < 0.01). There was no RASSF1A gene, and few P16 gene expressing in the control group. The demethylation effect could be found in the groups treated with hydralazine or both drugs, whereas no demethylation effect happened in the valproate group. Conclusion: The two drugs could synergistically re-express P16 and RASSF1A genes silenced in QBC939, and they exerted a great anti-tumour effect on QBC cells.
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.
