The Experts below are selected from a list of 3984 Experts worldwide ranked by ideXlab platform
Xinhua Liu - One of the best experts on this subject based on the ideXlab platform.
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histone demethylase jmjd3 regulates fibroblast like synoviocyte mediated proliferation and joint destruction in rheumatoid arthritis
The FASEB Journal, 2018Co-Authors: Wanwan Jia, Di Yang, Chenxi Xiao, Zheng Huang, Ming Qin, Mengwei Huang, Siyu Liu, Fen Long, Jianchun Mao, Xinhua LiuAbstract:Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.
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JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of pak1 a key mapk signaling component
Molecular Cancer, 2017Co-Authors: Xujun Liu, Xinhua Liu, Jie Ren, Ziran Yang, Jianguo Yang, Shumeng Liu, Fei Pei, Xiaohan Yang, Luyang SunAbstract:Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention.
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JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component
BMC, 2017Co-Authors: Xujun Liu, Xinhua Liu, Jie Ren, Ziran Yang, Jianguo Yang, Shumeng Liu, Fei PeiAbstract:Abstract Background Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. Methods We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. Results Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. Conclusions Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention
Steven A Weinman - One of the best experts on this subject based on the ideXlab platform.
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protein arginine methyl transferase 1 and jumonji c domain containing protein 6 dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice
Hepatology, 2018Co-Authors: Jie Zhao, Steven A Weinman, Abby Adams, Ben Roberts, Maura Oneil, Anusha Vittal, Timothy M Schmitt, Sean C Kumer, Josiah Cox, Irina TikhanovichAbstract:Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily PRMT1, and a demethylase JMJD6. The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte specific PRMT1 knockout mice we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of Hnf4α, an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the Hnf4α promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R=0.8, P<0.01) between arginine methylation levels and Hnf4α expression in these specimens suggesting that above mechanism is relevant in patients. Conclusion: Taken together these data suggest that PRMT1 inhibition such as induced by alcohol may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. This article is protected by copyright. All rights reserved.
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demethylase JMJD6 as a new regulator of interferon signaling effects of hcv and ethanol metabolism
Cellular and molecular gastroenterology and hepatology, 2018Co-Authors: Murali Ganesan, Irina Tikhanovich, Shiva Shankar Vangimalla, Raghubendra Singh Dagur, Weimin Wang, Larisa Poluektova, Yimin Sun, David F Mercer, Dean J Tuma, Steven A WeinmanAbstract:Background & Aims Alcohol-induced progression of hepatitis C virus (HCV) infection is related to dysfunction of innate immunity in hepatocytes. Endogenously produced interferon (IFN)α induces activation of interferon-stimulated genes (ISGs) via triggering of the Janus kinase–signal transducer and activator of transcription 1 (STAT1) pathway. This activation requires protein methyltransferase 1–regulated arginine methylation of STAT1. Here, we aimed to study whether STAT1 methylation also depended on the levels of demethylase jumonji domain-containing 6 protein (JMJD6) and whether ethanol and HCV affect JMJD6 expression in hepatocytes. Methods Huh7.5-CYP (RLW) cells and hepatocytes were exposed to acetaldehyde-generating system (AGS) and 50 mmol/L ethanol, respectively. JMJD6 messenger RNA and protein expression were measured by real-time polymerase chain reaction and Western blot. IFNα-activated cells either overexpressing JMJD6 or with knocked-down JMJD6 expression were tested for STAT1 methylation, ISG activation, and HCV RNA. In vivo studies have been performed on C57Bl/6 mice (expressing HCV structural proteins or not) or chimeric mice with humanized livers fed control or ethanol diets. Results AGS exposure to cells up-regulated JMJD6 expression in RLW cells. These results were corroborated by ethanol treatment of primary hepatocytes. The promethylating agent betaine reversed the effects of AGS/ethanol. Similar results were obtained in vivo, when mice were fed control/ethanol with and without betaine supplementation. Overexpression of JMJD6 suppressed STAT1 methylation, IFNα-induced ISG activation, and increased HCV-RNA levels. In contrast, JMJD6 silencing enhanced STAT1 methylation, ISG stimulation by IFNα, and attenuated HCV-RNA expression in Huh7.5 cells. Conclusions We conclude that arginine methylation of STAT1 is suppressed by JMJD6. Both HCV and acetaldehyde increase JMJD6 levels, thereby impairing STAT1 methylation and innate immunity protection in hepatocytes exposed to the virus and/or alcohol.
Irina Tikhanovich - One of the best experts on this subject based on the ideXlab platform.
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protein arginine methyl transferase 1 and jumonji c domain containing protein 6 dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice
Hepatology, 2018Co-Authors: Jie Zhao, Steven A Weinman, Abby Adams, Ben Roberts, Maura Oneil, Anusha Vittal, Timothy M Schmitt, Sean C Kumer, Josiah Cox, Irina TikhanovichAbstract:Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily PRMT1, and a demethylase JMJD6. The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte specific PRMT1 knockout mice we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of Hnf4α, an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the Hnf4α promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R=0.8, P<0.01) between arginine methylation levels and Hnf4α expression in these specimens suggesting that above mechanism is relevant in patients. Conclusion: Taken together these data suggest that PRMT1 inhibition such as induced by alcohol may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. This article is protected by copyright. All rights reserved.
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demethylase JMJD6 as a new regulator of interferon signaling effects of hcv and ethanol metabolism
Cellular and molecular gastroenterology and hepatology, 2018Co-Authors: Murali Ganesan, Irina Tikhanovich, Shiva Shankar Vangimalla, Raghubendra Singh Dagur, Weimin Wang, Larisa Poluektova, Yimin Sun, David F Mercer, Dean J Tuma, Steven A WeinmanAbstract:Background & Aims Alcohol-induced progression of hepatitis C virus (HCV) infection is related to dysfunction of innate immunity in hepatocytes. Endogenously produced interferon (IFN)α induces activation of interferon-stimulated genes (ISGs) via triggering of the Janus kinase–signal transducer and activator of transcription 1 (STAT1) pathway. This activation requires protein methyltransferase 1–regulated arginine methylation of STAT1. Here, we aimed to study whether STAT1 methylation also depended on the levels of demethylase jumonji domain-containing 6 protein (JMJD6) and whether ethanol and HCV affect JMJD6 expression in hepatocytes. Methods Huh7.5-CYP (RLW) cells and hepatocytes were exposed to acetaldehyde-generating system (AGS) and 50 mmol/L ethanol, respectively. JMJD6 messenger RNA and protein expression were measured by real-time polymerase chain reaction and Western blot. IFNα-activated cells either overexpressing JMJD6 or with knocked-down JMJD6 expression were tested for STAT1 methylation, ISG activation, and HCV RNA. In vivo studies have been performed on C57Bl/6 mice (expressing HCV structural proteins or not) or chimeric mice with humanized livers fed control or ethanol diets. Results AGS exposure to cells up-regulated JMJD6 expression in RLW cells. These results were corroborated by ethanol treatment of primary hepatocytes. The promethylating agent betaine reversed the effects of AGS/ethanol. Similar results were obtained in vivo, when mice were fed control/ethanol with and without betaine supplementation. Overexpression of JMJD6 suppressed STAT1 methylation, IFNα-induced ISG activation, and increased HCV-RNA levels. In contrast, JMJD6 silencing enhanced STAT1 methylation, ISG stimulation by IFNα, and attenuated HCV-RNA expression in Huh7.5 cells. Conclusions We conclude that arginine methylation of STAT1 is suppressed by JMJD6. Both HCV and acetaldehyde increase JMJD6 levels, thereby impairing STAT1 methylation and innate immunity protection in hepatocytes exposed to the virus and/or alcohol.
Alexander Wolf - One of the best experts on this subject based on the ideXlab platform.
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jumonji domain containing protein 6 JMJD6 modulates splicing and specifically interacts with arginine serine rich rs domains of sr and sr like proteins
Nucleic Acids Research, 2014Co-Authors: Astrid Heim, Benedikt M Kessler, Christina Grimm, Udo Muller, Simon Hausler, Mukram M Mackeen, Juliane Merl, Stefanie M Hauck, Christopher J Schofield, Alexander WolfAbstract:The Fe(II) and 2-oxoglutarate dependent oxygenase JMJD6 has been shown to hydroxylate lysine residues in the essential splice factor U2 auxiliary factor 65 kDa subunit (U2AF65) and to act as a modulator of alternative splicing. We describe further evidence for the role of JMJD6 in the regulation of pre-mRNA processing including interactions of JMJD6 with multiple arginine-serine-rich (RS)-domains of SR- and SR-related proteins including U2AF65, Luc7-like protein 3 (Luc7L3), SRSF11 and Acinus S', but not with the bona fide RS-domain of SRSF1. The identified JMJD6 target proteins are involved in different mRNA processing steps and play roles in exon dependent alternative splicing and exon definition. Moreover, we show that JMJD6 modifies splicing of a constitutive splice reporter, binds RNA derived from the reporter plasmid and punctually co-localises with nascent RNA. We propose that JMJD6 exerts its splice modulatory function by interacting with specific SR-related proteins during splicing in a RNA dependent manner.
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JMJD6 catalyses lysyl hydroxylation of u2af65 a protein associated with rna splicing
Science, 2009Co-Authors: Celia J Webby, Holger B Kramer, Benedikt M Kessler, Alexander Wolf, Natalia Gromak, Mathias Dreger, Michael L Nielsen, Corinna Schmitz, Danica Butler, John R YatesAbstract:The finding that the metazoan hypoxic response is regulated by oxygen-dependent posttranslational hydroxylations, which regulate the activity and lifetime of hypoxia-inducible factor (HIF), has raised the question of whether other hydroxylases are involved in the regulation of gene expression. We reveal that the splicing factor U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit (U2AF65) undergoes posttranslational lysyl-5-hydroxylation catalyzed by the Fe(II) and 2-oxoglutarate–dependent dioxygenase Jumonji domain-6 protein (JMJD6). JMJD6 is a nuclear protein that has an important role in vertebrate development and is a human homolog of the HIF asparaginyl-hydroxylase. JMJD6 is shown to change alternative RNA splicing of some, but not all, of the endogenous and reporter genes, supporting a specific role for JMJD6 in the regulation of RNA splicing.
Ryuji Hamamoto - One of the best experts on this subject based on the ideXlab platform.
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lysyl 5 hydroxylation a novel histone modification by jumonji domain containing 6 JMJD6
Journal of Biological Chemistry, 2013Co-Authors: Motoko Unoki, Akiko Masuda, Naoshi Dohmae, Kyohei Arita, Masanori Yoshimatsu, Yukiko Iwai, Yoshinori Fukui, Koji Ueda, Ryuji HamamotoAbstract:JMJD6 is reported to hydroxylate lysyl residues of a splicing factor, U2AF65. In this study, we found that JMJD6 hydroxylates histone lysyl residues. In vitro experiments showed that JMJD6 has a binding affinity to histone proteins and hydroxylates multiple lysyl residues of histone H3 and H4 tails. Using JMJD6 knock-out mouse embryos, we revealed that JMJD6 hydroxylates lysyl residues of histones H2A/H2B and H3/H4 in vivo by amino acid composition analysis. 5-Hydroxylysine was detected at the highest level in histones purified from murine testis, which expressed JMJD6 at a significantly high level among various tissues examined, and JMJD6 overexpression increased the amount of 5-hydroxylysine in histones in human embryonic kidney 293 cells. These results indicate that histones are additional substrates of JMJD6 in vivo. Because 5-hydroxylation of lysyl residues inhibited N-acetylation and N-methylation by an acetyltransferase and a methyltransferase, respectively, in vitro, histone 5-hydroxylation may have important roles in epigenetic regulation of gene transcription or chromosomal rearrangement.