Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism r...Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism research. We aimed to investigate the effect and mechanism of miR-362-3p on neuropathic pain in rats with chronic sciatic nerve injury (CCI). Methods: Neuropathic pain CCI rat model was established. Real-time-quantitative polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, intrathecal injection, Enzyme-linked immunosorbent assay (ELISA), and dual luciferase reporter gene assays were used to explore the role of miR-362-3p in neuropathic pain development and the relationship between miR-362-3p and JMJD1A (Jumonji domain-containing 1A). Results: In the CCI group, the miR-362-3p level was increased and JMJD1A level was reduced in spinal cords and isolated microglia. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) values were increased, the secretion of inflammatory factors was reduced, and the microglial marker Iba1 expression was decreased after intrathecal administration of miR-362-3p. miR-362-3p was observed to target JMJD1A. JMJD1A elevation abolished the inhibitory effects of miR-362-3p on neuropathic pain development. Conclusion: Intrathecal administration of miR-362-3p significantly relieved neuropathic pain in CCI rats and inhibited neuroinflammation possibly through regulating JMJD1A.展开更多
Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells(SSCs).The mechanisms underlying the transition from SSCs to sperm are largely unknown.Most stud...Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells(SSCs).The mechanisms underlying the transition from SSCs to sperm are largely unknown.Most studies utilize gene knockout mice to explain the mechanisms.However,the production of genetically engineered mice is costly and time-consuming.In this study,we presented a convenient research strategy using an RNA interference(RNAi)and testicular transplantation approach.Histone H3 lysine 9(H3K9)methylation was dynamically regulated during spermatogenesis.As Jumonji domain-containing protein 1A(JMJD1A)and Jumonji domain-containing protein 2C(JMJD2C)demethylases catalyze histone H3 lysine 9 dimethylation(H3K9me2),we firstly analyzed the expression profile of the two demethylases and then investigated their function.Using the convenient research strategy,we showed that normal spermatogenesis is disrupted due to the downregulated expression of both demethylases.These results suggest that this strategy might be a simple and alternative approach for analyzing spermatogenesis relative to the gene knockout mice strategy.展开更多
JMJD1C(Jumonji Domain Containing 1C), a member of the lysine demethylase 3(KDM3) family, is universally required for the survival of several types of acute myeloid leukemia(AML) cells with different genetic mutations,...JMJD1C(Jumonji Domain Containing 1C), a member of the lysine demethylase 3(KDM3) family, is universally required for the survival of several types of acute myeloid leukemia(AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.展开更多
Neuropathic pain(NP)is a chronic debilitating disease caused by nerve damage or various diseases,significantly impairs patients’quality of life.Super-enhancers(SEs)are important cis-regulatory elements,but how they a...Neuropathic pain(NP)is a chronic debilitating disease caused by nerve damage or various diseases,significantly impairs patients’quality of life.Super-enhancers(SEs)are important cis-regulatory elements,but how they affect NP remains elusive.Therefore,we aim to explore the molecular mechanism by which SEs are involved in NP progression and identify potential drug candidate targets.We first established a NP model in rats,and subsequently performed H3K27ac ChIP-Seq and RNA-Seq on their spinal cord tissues to analyze the active enhancers.By integrated analysis of ChIP-seq data and RNA-seq data,we clarified a series of SE-associated genes involved in NP progression.qPCR and double immunofluorescence staining results suggested that Jmjd1c mRNA and protein levels were significantly down-regulated in the NP model.In addition,a dual-luciferase reporter assay showed that KLF15 could activate Jmjd1c transcription by binding to the SE of Jmjd1c.Functionally,enhanced Jmjd1c can inhibit the levels of inflammatory cytokines such as IL-6,TNF-α,IL-1β,and inhibited the progression of NP,whereas silencing Jmjd1c had the opposite effect.Mechanistic exploration identified Jmjd1c exerted its anti-NP effect via positively regulating Socs3 expression by increasing the activity of H3K9 demethylation,and the Jmjd1c/Socs3/JAK/STAT3 regulatory pathway was finally validated as downstream effectors.In conclusion,our study suggests that SE-associated Jmjd1c was suppressed during NP progression due to the decreased recruitment of KLF15.The reduction of Jmjd1c downregulated Socs3 through the demethylation of H3K9 at Socs3 promoter region,leading to NP progression.展开更多
文摘Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism research. We aimed to investigate the effect and mechanism of miR-362-3p on neuropathic pain in rats with chronic sciatic nerve injury (CCI). Methods: Neuropathic pain CCI rat model was established. Real-time-quantitative polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, intrathecal injection, Enzyme-linked immunosorbent assay (ELISA), and dual luciferase reporter gene assays were used to explore the role of miR-362-3p in neuropathic pain development and the relationship between miR-362-3p and JMJD1A (Jumonji domain-containing 1A). Results: In the CCI group, the miR-362-3p level was increased and JMJD1A level was reduced in spinal cords and isolated microglia. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) values were increased, the secretion of inflammatory factors was reduced, and the microglial marker Iba1 expression was decreased after intrathecal administration of miR-362-3p. miR-362-3p was observed to target JMJD1A. JMJD1A elevation abolished the inhibitory effects of miR-362-3p on neuropathic pain development. Conclusion: Intrathecal administration of miR-362-3p significantly relieved neuropathic pain in CCI rats and inhibited neuroinflammation possibly through regulating JMJD1A.
基金financially supported by the Shandong Provincial Natural Science Foundation(No.ZR2021QC182).
文摘Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells(SSCs).The mechanisms underlying the transition from SSCs to sperm are largely unknown.Most studies utilize gene knockout mice to explain the mechanisms.However,the production of genetically engineered mice is costly and time-consuming.In this study,we presented a convenient research strategy using an RNA interference(RNAi)and testicular transplantation approach.Histone H3 lysine 9(H3K9)methylation was dynamically regulated during spermatogenesis.As Jumonji domain-containing protein 1A(JMJD1A)and Jumonji domain-containing protein 2C(JMJD2C)demethylases catalyze histone H3 lysine 9 dimethylation(H3K9me2),we firstly analyzed the expression profile of the two demethylases and then investigated their function.Using the convenient research strategy,we showed that normal spermatogenesis is disrupted due to the downregulated expression of both demethylases.These results suggest that this strategy might be a simple and alternative approach for analyzing spermatogenesis relative to the gene knockout mice strategy.
基金National Key R&D Program of China(grant 2021YFA1300100 to M.C.)Beijing Municipal Natural Science Foundation(grant JQ23024 to M.C)+2 种基金Leukemia and Lymphoma Society(grant 7021-20 to R.G.R)National Natural Science Foundation of China(grant 32300445 to Q.C.)Tsinghua-Peking Center for Life Sciences postdoctoral fellowship to Q.C..
文摘JMJD1C(Jumonji Domain Containing 1C), a member of the lysine demethylase 3(KDM3) family, is universally required for the survival of several types of acute myeloid leukemia(AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.
基金supported by Shandong Provincial Natural Science Foundation(China)(No.ZR2021QH063).
文摘Neuropathic pain(NP)is a chronic debilitating disease caused by nerve damage or various diseases,significantly impairs patients’quality of life.Super-enhancers(SEs)are important cis-regulatory elements,but how they affect NP remains elusive.Therefore,we aim to explore the molecular mechanism by which SEs are involved in NP progression and identify potential drug candidate targets.We first established a NP model in rats,and subsequently performed H3K27ac ChIP-Seq and RNA-Seq on their spinal cord tissues to analyze the active enhancers.By integrated analysis of ChIP-seq data and RNA-seq data,we clarified a series of SE-associated genes involved in NP progression.qPCR and double immunofluorescence staining results suggested that Jmjd1c mRNA and protein levels were significantly down-regulated in the NP model.In addition,a dual-luciferase reporter assay showed that KLF15 could activate Jmjd1c transcription by binding to the SE of Jmjd1c.Functionally,enhanced Jmjd1c can inhibit the levels of inflammatory cytokines such as IL-6,TNF-α,IL-1β,and inhibited the progression of NP,whereas silencing Jmjd1c had the opposite effect.Mechanistic exploration identified Jmjd1c exerted its anti-NP effect via positively regulating Socs3 expression by increasing the activity of H3K9 demethylation,and the Jmjd1c/Socs3/JAK/STAT3 regulatory pathway was finally validated as downstream effectors.In conclusion,our study suggests that SE-associated Jmjd1c was suppressed during NP progression due to the decreased recruitment of KLF15.The reduction of Jmjd1c downregulated Socs3 through the demethylation of H3K9 at Socs3 promoter region,leading to NP progression.
