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
Cell cycle regulation plays a critical role in plant growth and development.In this study,the role of a tomato cell cycle gene SlCycB1 has been characterized.Expression analysis revealed that SlCycB1 was mostly expres...Cell cycle regulation plays a critical role in plant growth and development.In this study,the role of a tomato cell cycle gene SlCycB1 has been characterized.Expression analysis revealed that SlCycB1 was mostly expressed in stem,root,and leaves,with relative lower expression in flower and fruit.Tomato plants overexpressing SlCycB1 exhibited a reduction in cell number and increased cell size leading to the growth retardation.Furthermore,yeast two-hybrid analysis and bimolecular fluorescence complementation revealed that SlCycB1 interacted with histone H3.2,an essential component of the nucleosome.Histone H3.2 was transcriptionally up-regulated in the SlCycB1 overexpressing tomato lines.Furthermore,the overexpression of histone H3.2 in transgenic plants showed similar phenotypes to SlCycB1 overexpressing lines.Based on these findings,we concluded that SlCycB1 overexpression altered tomato architecture in association with histone H3.2.展开更多
The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among th...The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFkB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase- dependent manner.展开更多
Circular RNAs can regulate the development and progression of ischemic cerebral disease.However,it remains unclear whether they play a role in acute ischemic stroke.To investigate the role of the circular RNA Rap1b(ci...Circular RNAs can regulate the development and progression of ischemic cerebral disease.However,it remains unclear whether they play a role in acute ischemic stroke.To investigate the role of the circular RNA Rap1b(circRap1b)in acute ischemic stroke,in this study we established an in vitro model of acute ischemia and hypoxia by subjecting HT22 cells to oxygen and glucose deprivation and a mouse model of acute ischemia and hypoxia by occluding the right carotid artery.We found that circRap1b expression was remarkably down-regulated in the hippocampal tissue of the mouse model and in the HT22 cell model.In addition,Hoxa5 expression was strongly up-regulated in response to circRap1b overexpression.Hoxa5 expression was low in the hippocampus of a mouse model of acute ischemia and in HT22-AIS cells,and inhibited HT22-AIS cell apoptosis.Importantly,we found that circRap1b promoted Hoxa5 transcription by recruiting the acetyltransferase Kat7 to induce H3K14ac modification in the Hoxa5 promoter region.Hoxa5 regulated neuronal apoptosis by activating transcription of Fam3a,a neuronal apoptosis-related protein.These results suggest that circRap1b regulates Hoxa5 transcription and expression,and subsequently Fam3a expression,ultimately inhibiting cell apoptosis.Lastly,we explored the potential clinical relevance of circRap1b and Hoxa5 in vivo.Taken together,these findings demonstrate the mechanism by which circRap1b inhibits neuronal apoptosis in acute ischemic stroke.展开更多
Cancer stem cells (CSCs) are tumor initiating cells within the tumor mass;that play a critical role in cancer pathogenesis. CSCs regulate cancer cell survival, metastatic potential, resistance to conventional radio-ch...Cancer stem cells (CSCs) are tumor initiating cells within the tumor mass;that play a critical role in cancer pathogenesis. CSCs regulate cancer cell survival, metastatic potential, resistance to conventional radio-chemotherapy, disease relapse and poor prognosis. Recent studies have established that the drug resistant cancers and cancer cell lines possess high stem cell like traits compared to their drug sensitive counterparts. Histone demethylases are recently been linked to drug induced reversible tolerant state in cancers. Lysine histone demethylases are enzymes those demethylate lysines in histones and can act as transcriptional repressors or activators. Apart from histones other cellular proteins like E2F1, Rb, STAT3 and p53 are also regulated by methylation and demethylation cycles. In cancer cells these enzymes regulate cell survival, migration, invasion, and proliferation. This review summarizes the current progress of research on the role of histone demethylases in supporting drug tolerant cancer stem cell state and their potential as a drug target.展开更多
SPIN1(spindlin 1)是一种组蛋白修饰阅读器蛋白,通过识别组蛋白H3第4位赖氨酸三甲基化(trimethylation of lysine 4 on histone H3 protein subunit,H3K4me3)促进核糖体RNA的表达,从而影响表观遗传的调控,以此发挥其生物学作用。SPIN1...SPIN1(spindlin 1)是一种组蛋白修饰阅读器蛋白,通过识别组蛋白H3第4位赖氨酸三甲基化(trimethylation of lysine 4 on histone H3 protein subunit,H3K4me3)促进核糖体RNA的表达,从而影响表观遗传的调控,以此发挥其生物学作用。SPIN1在多种恶性肿瘤中过表达,可受多种长链非编码RNA(long non-coding RNA,lncRNA)、微RNA(microRNA,miRNA)及环状RNA(circularRNA,circRNA)的负向调控,并可由转录因子腺病毒E2因子1(adenovirus E2 factor 1,E2F1)转录激活,通过Wnt、磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B,PI3K/Akt)、转染过程重排(rearrangement during transfection,RET)因子、鼠双微体基因-p53(murine double minute 2-p53,MDM2-p53)等与肿瘤发生相关的信号通路,促进肿瘤的发生、发展,并与不良预后密切相关。随着对SPIN1的研究越来越深入,发现SPIN1可作为多种恶性肿瘤治疗的潜在靶点。目前已开发出针对SPIN1和H3K4me3间相互作用的抑制剂,以此阻断SPIN1的致癌能力。展开更多
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.
基金This work was supported by grants from the National Key Research&Development Plan(Grant Nos.2021YFD12002012018YFD1000800)+4 种基金National Natural Science Foundation of China(Grant Nos.3199118231972426)Wuhan Frontier Projects for Applied Foundation(Grant No.2019020701011492)International Cooperation Promotion Plan of Shihezi University(Grant No.GJHZ202104)Key Project of Hubei Hongshan Laboratory(Grant No.2021hszd007).
文摘Cell cycle regulation plays a critical role in plant growth and development.In this study,the role of a tomato cell cycle gene SlCycB1 has been characterized.Expression analysis revealed that SlCycB1 was mostly expressed in stem,root,and leaves,with relative lower expression in flower and fruit.Tomato plants overexpressing SlCycB1 exhibited a reduction in cell number and increased cell size leading to the growth retardation.Furthermore,yeast two-hybrid analysis and bimolecular fluorescence complementation revealed that SlCycB1 interacted with histone H3.2,an essential component of the nucleosome.Histone H3.2 was transcriptionally up-regulated in the SlCycB1 overexpressing tomato lines.Furthermore,the overexpression of histone H3.2 in transgenic plants showed similar phenotypes to SlCycB1 overexpressing lines.Based on these findings,we concluded that SlCycB1 overexpression altered tomato architecture in association with histone H3.2.
文摘The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFkB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase- dependent manner.
基金supported by the Natural Science Foundation of Liaoning Province,No.2021-MS-061(to LZhang)。
文摘Circular RNAs can regulate the development and progression of ischemic cerebral disease.However,it remains unclear whether they play a role in acute ischemic stroke.To investigate the role of the circular RNA Rap1b(circRap1b)in acute ischemic stroke,in this study we established an in vitro model of acute ischemia and hypoxia by subjecting HT22 cells to oxygen and glucose deprivation and a mouse model of acute ischemia and hypoxia by occluding the right carotid artery.We found that circRap1b expression was remarkably down-regulated in the hippocampal tissue of the mouse model and in the HT22 cell model.In addition,Hoxa5 expression was strongly up-regulated in response to circRap1b overexpression.Hoxa5 expression was low in the hippocampus of a mouse model of acute ischemia and in HT22-AIS cells,and inhibited HT22-AIS cell apoptosis.Importantly,we found that circRap1b promoted Hoxa5 transcription by recruiting the acetyltransferase Kat7 to induce H3K14ac modification in the Hoxa5 promoter region.Hoxa5 regulated neuronal apoptosis by activating transcription of Fam3a,a neuronal apoptosis-related protein.These results suggest that circRap1b regulates Hoxa5 transcription and expression,and subsequently Fam3a expression,ultimately inhibiting cell apoptosis.Lastly,we explored the potential clinical relevance of circRap1b and Hoxa5 in vivo.Taken together,these findings demonstrate the mechanism by which circRap1b inhibits neuronal apoptosis in acute ischemic stroke.
文摘Cancer stem cells (CSCs) are tumor initiating cells within the tumor mass;that play a critical role in cancer pathogenesis. CSCs regulate cancer cell survival, metastatic potential, resistance to conventional radio-chemotherapy, disease relapse and poor prognosis. Recent studies have established that the drug resistant cancers and cancer cell lines possess high stem cell like traits compared to their drug sensitive counterparts. Histone demethylases are recently been linked to drug induced reversible tolerant state in cancers. Lysine histone demethylases are enzymes those demethylate lysines in histones and can act as transcriptional repressors or activators. Apart from histones other cellular proteins like E2F1, Rb, STAT3 and p53 are also regulated by methylation and demethylation cycles. In cancer cells these enzymes regulate cell survival, migration, invasion, and proliferation. This review summarizes the current progress of research on the role of histone demethylases in supporting drug tolerant cancer stem cell state and their potential as a drug target.
