Proper flowering time is essential for plant reproduction. Winter annual Arabidopsis thaliana needs ver-nalization before flowering, during which AtVILs （VIN3 and VRNS, components of PRC2 complex） mediate the H3K27 ...Proper flowering time is essential for plant reproduction. Winter annual Arabidopsis thaliana needs ver-nalization before flowering, during which AtVILs （VIN3 and VRNS, components of PRC2 complex） mediate the H3K27 tri- methylation at the FLC locus （a floral repressor） to repress the FLC expression and hence to induce flowering. However, how VILs （VIL, VERNALIZATION INSENSITIVE 3-LIKE） function in rice is unknown. Here we demonstrated that rice LC2 （OsVIL3） and OsVIL2 （two OsVILs, possible components of PRC2 complex） promote rice flowering. Our results showed that expressions of LC2 and OsVIL2 are induced by SD （short-day） conditions and both Ic2 mutant and OsVIL2-RNAi lines display delayed heading date, consistent with the reduced expression levels of Hdl and Hd3a. Interestingly, LC2 binds to the promoter region of a floral repressor OsLF and represses the OsLF expression via H3K27 tri-methylation modification. In addition, OsLF directly regulates the Hdl expression through binding to Hdl promoter. These results first demonstrated that the putative PRC2 in rice is involved in photoperiod flowering regulation, which is different from that of Arabidopsis, and revealed that LC2 binds the promoter region of target gene, presenting a possible mechanism of the recruitment pro-cess of PRC2 complex to its target genes. The studies provide informative clues on the epigenetic control of rice flowering.展开更多
Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected ...Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.展开更多
The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downreg...The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downregulation of lipolysis in small rat adipocytes upon incubation with exosomes and microvesicles (EMVs) released from large adipocytes and harbouring the glycosylphosphatidylinositol (GPI)-anchored proteins, Gce1 and CD73, transcripts specific for FSP27 and GPAT3, and microRNAs, miR-16 and miR-222 was demonstrated. Here the release of EMVs from large (but not small) primary and differentiated and human rat adipocytes in response to palmitate, H2O2 and the anti-diabetic sulfonylurea, glimepiride, is shown to be significantly reduced upon inhibition of histone H3 lysine9 methyltransferase G9a by trans-2-phenylcyclopropylamine (tPCPA) and histone H3 lysine4 demethylase LSD1 by BIX01294. Inhibition of EMV release by tPCPA and BIX01294 was not caused by apoptosis but accompanied by upregulation of the H2O2-induced stimulation of lipid synthesis and downregulation of lipolysis in large (but not small) primary and differentiated rat and human adipocytes. In contrast, the simultaneous presence of tPCPA and BIX-01294 had almost no effect on the induced release of EMVs and lipid metabolism. These findings argue for regulation of the release of EMVs harbouring specific GPI-anchored proteins, transcripts and microRNAs from rat and human adipocytes by histone H3 methylation at lysines 4 and 9 in interdependent fashion. Thus the EMV-mediated transfer of lipogenic and anti-lipolytic information between large and small adipocytes in response to certain physiological and pharmacological stimuli seems to be controlled by epigenetic mechanisms.展开更多
MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that...MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that they have profoundly important functions in brain development and pathological processes. For example, miR-124 plays an important role in inducing and maintaining neuronal identity through targeting at least two anti-neural factors. MicroRNAs have also been implicated in brain disorders, including brain tumors and neurodegenerative diseases. This review aims to present an overview of the expression profiles and functions of microRNAs in the developing brains of vertebrates.展开更多
目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病的作用及临床分析。方法:选择2017年1月至2019年7月在南方医科大学附属花都医院产科住院分娩的孕妇120例,其中60例PE妊娠被纳入PE组,60例正常足月妊娠被纳入正常对照组...目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病的作用及临床分析。方法:选择2017年1月至2019年7月在南方医科大学附属花都医院产科住院分娩的孕妇120例,其中60例PE妊娠被纳入PE组,60例正常足月妊娠被纳入正常对照组。分娩前ELISA检测血清,分娩后取胎盘组织进行HE染色、免疫组织化学、Real time-PCR和Western blot检测、全基因组甲基化测序(WGBS)、RNA-seq、Microarray分析、基因富集分析(GSEA)、甲基化DNA免疫共沉淀测序(MeDIP-Seq)。采用t检验和单因素方差分析,对数据进行统计分析。结果:两组胎盘中绒毛滋养细胞与绒毛外滋养细胞均表达有DNMT1、STAT3、PTEN及TSC2蛋白。与正常对照组相比,PE组血清中STAT3、PTEN、TSC2蛋白表达量显著降低,而DNMT1升高;胎盘组织中STAT3 mRNA、PTEN mRNA及TSC2 mRNA表达均降低,而DNMT1 mRNA升高,差异均有统计学意义(P<0.05)。WGBS结果显示PE组和正常对照组DNA甲基化水平比较,DNMT1(34.32±1.16 vs 22.31±1.24)、STAT3(28.36±1.33 vs 17.25±1.05)、PTEN(23.05±1.17 vs 13.33±0.71),TSC2(26.53±1.15 vs 15.28±1.43)差异均有统计学意义(P<0.05)。Microarray检测发现44个差异显著的基因,上调基因为18个,下调基因为26个。MeDIP-Seq结果显示PE组和正常对照组比较,胎盘组织中STAT3(15.69±1.88 vs 10.53±1.21)、PTEN(13.67±1.12 vs 9.38±1.04)和TSC2(16.84±1.51 vs 11.53±1.49)启动子区域甲基化水平均显著升高,差异有统计学意义(P<0.05)。GSEA分析证实与PI3K/AKT/MTOR信号通路有关。结论:滋养细胞STAT3是介导PI3K-AKT/mTOR信号轴引起PE发病的重要基因,STAT3可作为PE表观遗传学治疗的潜在靶点。展开更多
During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite ...During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNAindependent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax(TrxG) and Polycomb(PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.展开更多
文摘Proper flowering time is essential for plant reproduction. Winter annual Arabidopsis thaliana needs ver-nalization before flowering, during which AtVILs （VIN3 and VRNS, components of PRC2 complex） mediate the H3K27 tri- methylation at the FLC locus （a floral repressor） to repress the FLC expression and hence to induce flowering. However, how VILs （VIL, VERNALIZATION INSENSITIVE 3-LIKE） function in rice is unknown. Here we demonstrated that rice LC2 （OsVIL3） and OsVIL2 （two OsVILs, possible components of PRC2 complex） promote rice flowering. Our results showed that expressions of LC2 and OsVIL2 are induced by SD （short-day） conditions and both Ic2 mutant and OsVIL2-RNAi lines display delayed heading date, consistent with the reduced expression levels of Hdl and Hd3a. Interestingly, LC2 binds to the promoter region of a floral repressor OsLF and represses the OsLF expression via H3K27 tri-methylation modification. In addition, OsLF directly regulates the Hdl expression through binding to Hdl promoter. These results first demonstrated that the putative PRC2 in rice is involved in photoperiod flowering regulation, which is different from that of Arabidopsis, and revealed that LC2 binds the promoter region of target gene, presenting a possible mechanism of the recruitment pro-cess of PRC2 complex to its target genes. The studies provide informative clues on the epigenetic control of rice flowering.
基金supported by National Natural Science Foundation of China(11932012,81870790 and 31801233)Science and Technology Commission of Shanghai Municipality(18441903600)+1 种基金Clinical Research Plan of SHDC(No.SHDC2020CR3009A)Innovative Research Team of High-level Local Universities in Shanghai(SSMU-ZDCX20180902)。
文摘Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.
文摘The transfer of proteins and nucleic acids from donor to acceptor cells via small membrane vesicles has been implicated with (patho)physiological consequences. Previously the upregulation of esterification and downregulation of lipolysis in small rat adipocytes upon incubation with exosomes and microvesicles (EMVs) released from large adipocytes and harbouring the glycosylphosphatidylinositol (GPI)-anchored proteins, Gce1 and CD73, transcripts specific for FSP27 and GPAT3, and microRNAs, miR-16 and miR-222 was demonstrated. Here the release of EMVs from large (but not small) primary and differentiated and human rat adipocytes in response to palmitate, H2O2 and the anti-diabetic sulfonylurea, glimepiride, is shown to be significantly reduced upon inhibition of histone H3 lysine9 methyltransferase G9a by trans-2-phenylcyclopropylamine (tPCPA) and histone H3 lysine4 demethylase LSD1 by BIX01294. Inhibition of EMV release by tPCPA and BIX01294 was not caused by apoptosis but accompanied by upregulation of the H2O2-induced stimulation of lipid synthesis and downregulation of lipolysis in large (but not small) primary and differentiated rat and human adipocytes. In contrast, the simultaneous presence of tPCPA and BIX-01294 had almost no effect on the induced release of EMVs and lipid metabolism. These findings argue for regulation of the release of EMVs harbouring specific GPI-anchored proteins, transcripts and microRNAs from rat and human adipocytes by histone H3 methylation at lysines 4 and 9 in interdependent fashion. Thus the EMV-mediated transfer of lipogenic and anti-lipolytic information between large and small adipocytes in response to certain physiological and pharmacological stimuli seems to be controlled by epigenetic mechanisms.
基金the Key Basic Research Developing Project of China (973 Project), No.2007CB947001the State High Technology Development and Research Project of China (863 Project), No.2008AA02Z115+1 种基金the Key Program of National Natural Science Foundation of China, No.30430240Shanghai Metropolitan Fund for Research and Development, No. 04DZ14005,04JC14096
文摘MicroRNAs are abundant in the brains of vertebrates and some show a brain-specific or brain-enriched expression pattern. Because microRNAs regulate the expression of hundreds of target genes, it is not surprising that they have profoundly important functions in brain development and pathological processes. For example, miR-124 plays an important role in inducing and maintaining neuronal identity through targeting at least two anti-neural factors. MicroRNAs have also been implicated in brain disorders, including brain tumors and neurodegenerative diseases. This review aims to present an overview of the expression profiles and functions of microRNAs in the developing brains of vertebrates.
文摘目的:探讨滋养细胞STAT3基因介导表观遗传学调控对子痫前期(PE)发病的作用及临床分析。方法:选择2017年1月至2019年7月在南方医科大学附属花都医院产科住院分娩的孕妇120例,其中60例PE妊娠被纳入PE组,60例正常足月妊娠被纳入正常对照组。分娩前ELISA检测血清,分娩后取胎盘组织进行HE染色、免疫组织化学、Real time-PCR和Western blot检测、全基因组甲基化测序(WGBS)、RNA-seq、Microarray分析、基因富集分析(GSEA)、甲基化DNA免疫共沉淀测序(MeDIP-Seq)。采用t检验和单因素方差分析,对数据进行统计分析。结果:两组胎盘中绒毛滋养细胞与绒毛外滋养细胞均表达有DNMT1、STAT3、PTEN及TSC2蛋白。与正常对照组相比,PE组血清中STAT3、PTEN、TSC2蛋白表达量显著降低,而DNMT1升高;胎盘组织中STAT3 mRNA、PTEN mRNA及TSC2 mRNA表达均降低,而DNMT1 mRNA升高,差异均有统计学意义(P<0.05)。WGBS结果显示PE组和正常对照组DNA甲基化水平比较,DNMT1(34.32±1.16 vs 22.31±1.24)、STAT3(28.36±1.33 vs 17.25±1.05)、PTEN(23.05±1.17 vs 13.33±0.71),TSC2(26.53±1.15 vs 15.28±1.43)差异均有统计学意义(P<0.05)。Microarray检测发现44个差异显著的基因,上调基因为18个,下调基因为26个。MeDIP-Seq结果显示PE组和正常对照组比较,胎盘组织中STAT3(15.69±1.88 vs 10.53±1.21)、PTEN(13.67±1.12 vs 9.38±1.04)和TSC2(16.84±1.51 vs 11.53±1.49)启动子区域甲基化水平均显著升高,差异有统计学意义(P<0.05)。GSEA分析证实与PI3K/AKT/MTOR信号通路有关。结论:滋养细胞STAT3是介导PI3K-AKT/mTOR信号轴引起PE发病的重要基因,STAT3可作为PE表观遗传学治疗的潜在靶点。
文摘During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNAindependent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax(TrxG) and Polycomb(PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
