Arsenic (As) is an omnipresent metalloid toxicant,which has elicited serious environmental pollution and health risky problems.Previous studies have uncovered that the As exposure could also cause markedly reduction o...Arsenic (As) is an omnipresent metalloid toxicant,which has elicited serious environmental pollution and health risky problems.Previous studies have uncovered that the As exposure could also cause markedly reduction of serum triglycerides in mice.However,the regulation mechanisms are still largely unknown.The present study is aimed to elucidate the molecular mechanisms of lncRNAs in As-induced lipid metabolic disequilibrium.We demonstrated that lncRNA PU.1 AS was significantly induced in the liver of As-feed mice companied with lower serum triglycerides contents;further in vitro experiment confirmed that PU.1 AS regulated liver cells lipid accumulation by nile red fluorescence staining.Intensive mechanistic investigations illustrated that PU.1 AS could interact with EZH2 protein to regulate its downstream target gene expression,and Asinduced PU.1 AS attenuated EZH2-supppressed Sirt6 expression,thereafter leading to a decreased SREBP-1c protein expression,as well as the diminished synthesis of triglycerides in hepatocytes.In conclusion,this study provided a new lncRNA-related regulatory signaling pathway participating in As-induced abnormal lipid metabolism.展开更多
Microglial activation occurs in divergent neuropathological conditions.Such microglial event has the key involvement in the progression of CNS diseases.However,the transcriptional mechanism governing microglial activa...Microglial activation occurs in divergent neuropathological conditions.Such microglial event has the key involvement in the progression of CNS diseases.However,the transcriptional mechanism governing microglial activation remains poorly understood.Here,we investigate the microglial response to traumatic injuryinduced neurodegeneration by the 3D fluorescence imaging technique.We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation,as their specific post-developmental deletion in microglia abolishes the process.Mechanistically,we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhaneed expression during microglial activation.Moreover,IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes.This action of cooperative transcription can be further verified bio chemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA.Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14000000)the National Natural Science Foundation of China(Nos.21507154,21425731,21637004 and 81570542)
文摘Arsenic (As) is an omnipresent metalloid toxicant,which has elicited serious environmental pollution and health risky problems.Previous studies have uncovered that the As exposure could also cause markedly reduction of serum triglycerides in mice.However,the regulation mechanisms are still largely unknown.The present study is aimed to elucidate the molecular mechanisms of lncRNAs in As-induced lipid metabolic disequilibrium.We demonstrated that lncRNA PU.1 AS was significantly induced in the liver of As-feed mice companied with lower serum triglycerides contents;further in vitro experiment confirmed that PU.1 AS regulated liver cells lipid accumulation by nile red fluorescence staining.Intensive mechanistic investigations illustrated that PU.1 AS could interact with EZH2 protein to regulate its downstream target gene expression,and Asinduced PU.1 AS attenuated EZH2-supppressed Sirt6 expression,thereafter leading to a decreased SREBP-1c protein expression,as well as the diminished synthesis of triglycerides in hepatocytes.In conclusion,this study provided a new lncRNA-related regulatory signaling pathway participating in As-induced abnormal lipid metabolism.
基金State Key Laboratory of Membrane Biology,IDG/McGovern Institute for Brain Research,Center for Life Sciences and School of Life Sciences at Peking University,and National Natural Science Foundation of China to J.Yang(Grant Nos.31522024 and 31771111).
文摘Microglial activation occurs in divergent neuropathological conditions.Such microglial event has the key involvement in the progression of CNS diseases.However,the transcriptional mechanism governing microglial activation remains poorly understood.Here,we investigate the microglial response to traumatic injuryinduced neurodegeneration by the 3D fluorescence imaging technique.We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation,as their specific post-developmental deletion in microglia abolishes the process.Mechanistically,we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhaneed expression during microglial activation.Moreover,IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes.This action of cooperative transcription can be further verified bio chemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA.Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.
