The Experts below are selected from a list of 21327 Experts worldwide ranked by ideXlab platform
Shan Zheng - One of the best experts on this subject based on the ideXlab platform.
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microrna 29b 142 5p contribute to the pathogenesis of biliary atresia by regulating the ifn γ gene
Cell Death and Disease, 2018Co-Authors: Yifan Yang, Zhu Jin, Rui Dong, Chao Zheng, Yanlei Huang, Yijie Zheng, Zhen Shen, Gong Chen, Xiaoying Luo, Shan ZhengAbstract:Biliary atresia is one of the most common liver disease in infancy. The cause and pathogenesis remain largely unknown. This study aimed to investigate the potential regulatory effect of miR-29b/142-5p on IFN-γ gene methylation. miRNAs microarray was performed on four pairs of liver and blood specimens from biliary atresia and choledochal cysts. We found the overexpression of miR-142-5p and mRNA level of DNA methyltransferase (DNMT) 1, and miR-29b and DNMT3a/DNMT3b were significantly negatively correlated in biliary atresia livers. Meanwhile, the methylation of the LINE-1, ALU and SAT2 repetitive sequences and the IFN-γ promoter was lower, but the expression of IFN-γ was upregulated. After transfected with DNMTs siRNAs, downregulation of DNMTs exerted a significant hypomethylating effect on the repetitive sequences, which led to upregulation of IFN-γ in Jurkat cells. The direct interactions between miR-29b and DNMT3a/3b, and miR-142-5p and DNMT1 were identified using luciferase reporter assays. By transfecting mimics of miR-29b/142-5p into Jurkat cells, we found overexpression of miR-29b/142-5p markedly suppressed expression of DNMTs. Furthermore, the methylation of repetitive sequences and the IFN-γ promoter region were remarkably downregulated, and with elevated IFN-γ expression. After transfecting the miRNA inhibitors, the levels of DNMTs and the methylation of the IFN-γ gene promoter region was upregulated, while levels of IFN-γ were markedly suppressed. Our study suggested that miRNA-29b/142-5p overexpression and targeted inhibition of DNMTs expression resulted in decreased overall gene methylation and overexpression of the methylation-sensitive IFN-γ gene.
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MicroRNA-29b/142-5p contribute to the pathogenesis of biliary atresia by regulating the IFN-γ gene
Nature Publishing Group, 2018Co-Authors: Yifan Yang, Zhu Jin, Rui Dong, Chao Zheng, Yanlei Huang, Yijie Zheng, Zhen Shen, Gong Chen, Xiaoying Luo, Shan ZhengAbstract:Abstract Biliary atresia is one of the most common liver disease in infancy. The cause and pathogenesis remain largely unknown. This study aimed to investigate the potential regulatory effect of miR-29b/142-5p on IFN-γ gene methylation. miRNAs microarray was performed on four pairs of liver and blood specimens from biliary atresia and choledochal cysts. We found the overexpression of miR-142-5p and mRNA level of DNA methyltransferase (DNMT) 1, and miR-29b and DNMT3a/DNMT3b were significantly negatively correlated in biliary atresia livers. Meanwhile, the methylation of the LINE-1, ALU and SAT2 repetitive sequences and the IFN-γ promoter was lower, but the expression of IFN-γ was upregulated. After transfected with DNMTs siRNAs, downregulation of DNMTs exerted a significant hypomethylating effect on the repetitive sequences, which led to upregulation of IFN-γ in Jurkat cells. The direct interactions between miR-29b and DNMT3a/3b, and miR-142-5p and DNMT1 were identified using luciferase reporter assays. By transfecting mimics of miR-29b/142-5p into Jurkat cells, we found overexpression of miR-29b/142-5p markedly suppressed expression of DNMTs. Furthermore, the methylation of repetitive sequences and the IFN-γ promoter region were remarkably downregulated, and with elevated IFN-γ expression. After transfecting the miRNA inhibitors, the levels of DNMTs and the methylation of the IFN-γ gene promoter region was upregulated, while levels of IFN-γ were markedly suppressed. Our study suggested that miRNA-29b/142-5p overexpression and targeted inhibition of DNMTs expression resulted in decreased overall gene methylation and overexpression of the methylation-sensitive IFN-γ gene
Yifan Yang - One of the best experts on this subject based on the ideXlab platform.
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microrna 29b 142 5p contribute to the pathogenesis of biliary atresia by regulating the ifn γ gene
Cell Death and Disease, 2018Co-Authors: Yifan Yang, Zhu Jin, Rui Dong, Chao Zheng, Yanlei Huang, Yijie Zheng, Zhen Shen, Gong Chen, Xiaoying Luo, Shan ZhengAbstract:Biliary atresia is one of the most common liver disease in infancy. The cause and pathogenesis remain largely unknown. This study aimed to investigate the potential regulatory effect of miR-29b/142-5p on IFN-γ gene methylation. miRNAs microarray was performed on four pairs of liver and blood specimens from biliary atresia and choledochal cysts. We found the overexpression of miR-142-5p and mRNA level of DNA methyltransferase (DNMT) 1, and miR-29b and DNMT3a/DNMT3b were significantly negatively correlated in biliary atresia livers. Meanwhile, the methylation of the LINE-1, ALU and SAT2 repetitive sequences and the IFN-γ promoter was lower, but the expression of IFN-γ was upregulated. After transfected with DNMTs siRNAs, downregulation of DNMTs exerted a significant hypomethylating effect on the repetitive sequences, which led to upregulation of IFN-γ in Jurkat cells. The direct interactions between miR-29b and DNMT3a/3b, and miR-142-5p and DNMT1 were identified using luciferase reporter assays. By transfecting mimics of miR-29b/142-5p into Jurkat cells, we found overexpression of miR-29b/142-5p markedly suppressed expression of DNMTs. Furthermore, the methylation of repetitive sequences and the IFN-γ promoter region were remarkably downregulated, and with elevated IFN-γ expression. After transfecting the miRNA inhibitors, the levels of DNMTs and the methylation of the IFN-γ gene promoter region was upregulated, while levels of IFN-γ were markedly suppressed. Our study suggested that miRNA-29b/142-5p overexpression and targeted inhibition of DNMTs expression resulted in decreased overall gene methylation and overexpression of the methylation-sensitive IFN-γ gene.
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MicroRNA-29b/142-5p contribute to the pathogenesis of biliary atresia by regulating the IFN-γ gene
Nature Publishing Group, 2018Co-Authors: Yifan Yang, Zhu Jin, Rui Dong, Chao Zheng, Yanlei Huang, Yijie Zheng, Zhen Shen, Gong Chen, Xiaoying Luo, Shan ZhengAbstract:Abstract Biliary atresia is one of the most common liver disease in infancy. The cause and pathogenesis remain largely unknown. This study aimed to investigate the potential regulatory effect of miR-29b/142-5p on IFN-γ gene methylation. miRNAs microarray was performed on four pairs of liver and blood specimens from biliary atresia and choledochal cysts. We found the overexpression of miR-142-5p and mRNA level of DNA methyltransferase (DNMT) 1, and miR-29b and DNMT3a/DNMT3b were significantly negatively correlated in biliary atresia livers. Meanwhile, the methylation of the LINE-1, ALU and SAT2 repetitive sequences and the IFN-γ promoter was lower, but the expression of IFN-γ was upregulated. After transfected with DNMTs siRNAs, downregulation of DNMTs exerted a significant hypomethylating effect on the repetitive sequences, which led to upregulation of IFN-γ in Jurkat cells. The direct interactions between miR-29b and DNMT3a/3b, and miR-142-5p and DNMT1 were identified using luciferase reporter assays. By transfecting mimics of miR-29b/142-5p into Jurkat cells, we found overexpression of miR-29b/142-5p markedly suppressed expression of DNMTs. Furthermore, the methylation of repetitive sequences and the IFN-γ promoter region were remarkably downregulated, and with elevated IFN-γ expression. After transfecting the miRNA inhibitors, the levels of DNMTs and the methylation of the IFN-γ gene promoter region was upregulated, while levels of IFN-γ were markedly suppressed. Our study suggested that miRNA-29b/142-5p overexpression and targeted inhibition of DNMTs expression resulted in decreased overall gene methylation and overexpression of the methylation-sensitive IFN-γ gene
Frank Lyko - One of the best experts on this subject based on the ideXlab platform.
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DNMT1 has an essential function despite the absence of CpG DNA methylation in the red flour beetle Tribolium castaneum
Scientific Reports, 2018Co-Authors: Nora K. E. Schulz, C. Isabel Wagner, Maike F. Diddens-de Buhr, Julia Ebeling, Gunter Raddatz, Frank Lyko, Joachim KurtzAbstract:Epigenetic mechanisms, such as CpG DNA methylation enable phenotypic plasticity and rapid adaptation to changing environments. CpG DNA methylation is established by DNA methyltransferases (DNMTs), which are well conserved across vertebrates and invertebrates. There are insects with functional DNA methylation despite lacking a complete set of Dnmts . But at least one of the enzymes, DNMT1, appears to be required to maintain an active DNA methylation system. The red flour beetle, Tribolium castaneum , lacks Dnmt3 but possesses DNMT1 and it has been controversial whether it has a functional DNA methylation system. Using whole genome bisulfite sequencing, we did not find any defined patterns of CpG DNA methylation in embryos. Nevertheless, we found DNMT1 expressed throughout the entire life cycle of the beetle, with mRNA transcripts significantly more abundant in eggs and ovaries. A maternal knockdown of DNMT1 caused a developmental arrest in offspring embryos. We show that DNMT1 plays an essential role in T. castaneum embryos and that its downregulation leads to an early developmental arrest. This function appears to be unrelated to DNA methylation, since we did not find any evidence for this modification. This strongly suggests an alternative role of this protein.
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the dna methyltransferase family a versatile toolkit for epigenetic regulation
Nature Reviews Genetics, 2018Co-Authors: Frank LykoAbstract:The DNA methyltransferase (DNMT) family comprises a conserved set of DNA-modifying enzymes that have a central role in epigenetic gene regulation. Recent studies have shown that the functions of the canonical DNMT enzymes - DNMT1, DNMT3A and DNMT3B - go beyond their traditional roles of establishing and maintaining DNA methylation patterns. This Review analyses how molecular interactions and changes in gene copy numbers modulate the activity of DNMTs in diverse gene regulatory functions, including transcriptional silencing, transcriptional activation and post-transcriptional regulation by DNMT2-dependent tRNA methylation. This mechanistic diversity enables the DNMT family to function as a versatile toolkit for epigenetic regulation.
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molecular modeling and molecular dynamics studies of hydralazine with human dna methyltransferase 1
ChemMedChem, 2009Co-Authors: Narender Singh, Frank Lyko, Alfonso Duenasgonzalez, Jose L MedinafrancoAbstract:DNA methyltransferases (DNMTs) are a family of enzymes that methylate DNA at the C5 position of cytosine residues, and their inhibition is a promising strategy for the treatment of various developmental and proliferative diseases, particularly cancers. In the present study, a binding model for hydralazine, with a validated homology model of human DNMT, was developed by the use of automated molecular docking and molecular dynamics simulations. The docking protocol was validated by predicting the binding mode of 2'-deoxycytidine, 5-azacytidine, and 5-aza-2'-deoxycytidine. The inhibitory activity of hydralazine toward DNMT may be rationalized at the molecular level by similar interactions within the binding pocket (e.g., by a similar pharmacophore) as established by substrate-like deoxycytidine analogues. These interactions involve a complex network of hydrogen bonds with arginine and glutamic acid residues that also play a major role in the mechanism of DNA methylation. Despite the different scaffolds of other non-nucleoside DNMT inhibitors such as procaine and procainamide, the current modeling work reveals that these drugs exhibit similar interactions within the DNMT1 binding site. These findings are valuable in guiding the rational design and virtual screening of novel DNMT inhibitors.
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Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila
Nature Genetics, 1999Co-Authors: Frank Lyko, Bernard H. Ramsahoye, Helena Kashevsky, Matthew Tudor, Mary-ann Mastrangelo, Terry L. Orr-weaver, Rudolf JaenischAbstract:CpG methylation is essential for mouse development^ 1 as well as gene regulation and genome stability^ 2 , 3 , 4 , 5 . Many features of mammalian DNA methylation are consistent with the action of a de novo methyltransferase that establishes methylation patterns during early development and the post-replicative maintenance of these patterns by a maintenance methyltransferase^ 6 . The mouse methyltransferase DNMT1 (encoded by Dnmt ) shows a preference for hemimethylated substrates in vitro , making the enzyme a candidate for a maintenance methyltransferase^ 7 , 8 . DNMT1 also has de novo methylation activity in vitro ^ 9 , but the significance of this finding is unclear, because mouse embryonic stem (ES) cells contain a de novo methylating activity unrelated to DNMT1 (ref. 10 ). Recently, the Dnmt3 family of methyltransferases has been identified and shown in vitro to catalyse de novo methylation^ 11 . To analyse the function of these enzymes, we expressed Dnmt and Dnmt3a in transgenic Drosophila melanogaster . The absence of endogenous methylation in Drosophila ^ 12 , 13 facilitates detection of experimentally induced methylation changes. In this system, Dnmt3a functioned as a de novo methyltransferase, whereas DNMT1 had no detectable de novo methylation activity. When co-expressed, DNMT1 and Dnmt3a cooperated to establish and maintain methylation patterns. Genomic DNA methylation impaired the viability of transgenic flies, suggesting that cytosine methylation has functional consequences for Drosophila development.
Bernard H. Ramsahoye - One of the best experts on this subject based on the ideXlab platform.
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targeting of 5 aza 2 deoxycytidine residues by chromatin associated DNMT1 induces proteasomal degradation of the free enzyme
Nucleic Acids Research, 2010Co-Authors: Katan Patel, Jacqueline Dickson, Shahida Din, Kenneth G Macleod, Duncan I Jodrell, Bernard H. RamsahoyeAbstract:5-Aza-2'-deoxycytidine (5-aza-dC) is a nucleoside analogue with cytotoxic and DNA demethylating effects. Here we show that 5-aza-dC induces the proteasomal degradation of free (non-chromatin bound) DNMT1 through a mechanism which is dependent on DNA synthesis and the targeting of incorporated 5-aza-dC residues by DNMT1 itself. Thus, 5-aza-dC induces DNMT1 degradation in wild-type mouse ES cells, but not in Dnmt [3a(-/-), 3b(-/-)] mouse ES cells which express DNMT1 but lack DNA methylation (<0.7% of CpG methylated) and contain few hemi-methylated CpG sites, these being the preferred substrates for DNMT1. We suggest that adducts formed between DNMT1 and 5-aza-dC molecules in DNA induce a ubiquitin-E3 ligase activity which preferentially targets free DNMT1 molecules for degradation by the proteasome. The proteasome inhibitor MG132 prevents DNMT1 degradation and reduces hypomethylation induced by 5-aza-dC.
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Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila
Nature Genetics, 1999Co-Authors: Frank Lyko, Bernard H. Ramsahoye, Helena Kashevsky, Matthew Tudor, Mary-ann Mastrangelo, Terry L. Orr-weaver, Rudolf JaenischAbstract:CpG methylation is essential for mouse development^ 1 as well as gene regulation and genome stability^ 2 , 3 , 4 , 5 . Many features of mammalian DNA methylation are consistent with the action of a de novo methyltransferase that establishes methylation patterns during early development and the post-replicative maintenance of these patterns by a maintenance methyltransferase^ 6 . The mouse methyltransferase DNMT1 (encoded by Dnmt ) shows a preference for hemimethylated substrates in vitro , making the enzyme a candidate for a maintenance methyltransferase^ 7 , 8 . DNMT1 also has de novo methylation activity in vitro ^ 9 , but the significance of this finding is unclear, because mouse embryonic stem (ES) cells contain a de novo methylating activity unrelated to DNMT1 (ref. 10 ). Recently, the Dnmt3 family of methyltransferases has been identified and shown in vitro to catalyse de novo methylation^ 11 . To analyse the function of these enzymes, we expressed Dnmt and Dnmt3a in transgenic Drosophila melanogaster . The absence of endogenous methylation in Drosophila ^ 12 , 13 facilitates detection of experimentally induced methylation changes. In this system, Dnmt3a functioned as a de novo methyltransferase, whereas DNMT1 had no detectable de novo methylation activity. When co-expressed, DNMT1 and Dnmt3a cooperated to establish and maintain methylation patterns. Genomic DNA methylation impaired the viability of transgenic flies, suggesting that cytosine methylation has functional consequences for Drosophila development.
Enhua Wang - One of the best experts on this subject based on the ideXlab platform.
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dna methyltransferase 1 3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor alpha breast cancer susceptibility gene 1 and poor prognosis
Molecular Carcinogenesis, 2015Co-Authors: Qinghuan Xiao, Xuefeng Bai, Zhiguo Song, Lin Zhao, Jie Ren, Mingli Sun, Xiaojian Liu, Yuanyuan Yan, Enhua WangAbstract:DNA methyltransferases (DNMTs), including DNMT1, 3a, and 3b, play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of DNMTs is associated with the development of breast cancer. This study aimed to explore the clinical significance of DNMT proteins in sporadic breast cancer. We investigated the expression of DNMT1, 3a, and 3b in 256 breast cancer and 36 breast fibroadenoma, using immunohistochemistry. The expression of DNMT1 and 3a was significantly higher in breast cancer than in fibroadenoma. In breast cancer, the expression of DNMT1 was significantly correlated with lymph node metastasis (P = 0.020), and the expression of DNMT3a and 3b was significantly correlated with advanced clinical stages (P = 0.046 and 0.012, respectively). Overexpression of DNMT1/3a was correlated with promoter hypermethylation and reduced expression of ERα and BRCA1. The expression levels of DNMT1 or DNMT3a were associated with a significantly shorter DFS or OS in a subgroup of breast cancer patients (patients with the age ≤50 years old, ERα-negative status, or HER2-postive status). The expression of DNMT1 or a combined expression of DNMT1 and 3a was associated with poor prognosis in patients who received chemotherapy and endocrine therapy, but not in patients who received chemotherapy alone. These findings suggest that DNMT1 and 3a may be involved in the progression and prognosis of sporadic breast cancer.
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clinicopathological significance and prognostic value of dna methyltransferase 1 3a and 3b expressions in sporadic epithelial ovarian cancer
PLOS ONE, 2012Co-Authors: Xuefeng Bai, Zhiguo Song, Lin Zhao, Haishan Zhao, Weifan Yao, Desheng Huang, Enhua Wang, Zhihong Zheng, Minjie WeiAbstract:Altered DNA methylation of tumor suppressor gene promoters plays a role in human carcinogenesis and DNA methyltransferases (DNMTs) are responsible for it. This study aimed to determine aberrant expression of DNMT1, DNMT3a, and DNMT3b in benign and malignant ovarian tumor tissues for their association with clinicopathological significance and prognostic value. A total of 142 ovarian cancers and 44 benign ovarian tumors were recruited for immunohistochemical analysis of their expression. The data showed that expression of DNMT1, DNMT3a, and DNMT3b was observed in 76 (53.5%), 92 (64.8%) and 79 (55.6%) of 142 cases of ovarian cancer tissues, respectively. Of the serious tumors, DNMT3a protein expression was significantly higher than that in benign tumor samples (P=0.001); DNMT3b was marginally significant down regulated in ovarian cancers compared to that of the benign tumors (P=0.054); DNMT1 expression has no statistical difference between ovarian cancers and benign tumor tissues (P=0.837). Of the mucious tumors, the expression of DNMT3a, DNMT3b, and DNMT1 was not different between malignant and benign tumors. Moreover, DNMT1 expression was associated with DNMT3b expression (P=0.020, r=0.195). DNMT1 expression was associated with age of the patients, menopause status, and tumor localization, while DNMT3a expression was associated with histological types and serum CA125 levels and DNMT3b expression was associated with lymph node metastasis. In addition, patients with DNMT1 or DNMT3b expression had a trend of better survival than those with negative expression. Co-expression of DNMT1 and DNMT3b was significantly associated with better overall survival (P=0.014). The data from this study provided the first evidence for differential expression of DNMTs proteins in ovarian cancer tissues and their associations with clinicopathological and survival data in sporadic ovarian cancer patients.