Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer...Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.展开更多
Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study inv...Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications,suggesting their advantage in DR treatment.By single-cell RNA-sequencing analysis and immunostaining,we observed a high expression of GLP-1R in retinal endothelial cells,which was down-regulated under diabetic conditions.Treatment of GLP-1 RAs significantly restored the receptor expression,resulting in an improvement in retinal degeneration,vascular tortuosity,avascular vessels,and vascular integrity in diabetic mice.GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs.Additionally,the treatment attenuated STING signaling activation in retinal endothelial cells,which is typically activated by leaked mitochondrial DNA.Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes.Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling.This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.82172723)the Natural Science Foundation of Sichuan(Grant Nos.2023NSFSC1828 and 2022NSFSC1289)+2 种基金the“Xinglin Scholar”Scientific Research Promotion Plan of Chengdu University of Transitional Chinese Medicine(Grant No.BSH2021003)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-D-202209)the Research Funding of Department of Science and Technology of Qinghai Province(Grant No.2023-ZJ-729)。
文摘Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.
基金supported by grants from the National Natural Science Foundation of China(82000782,82270886,82070811)the Foster Program for NSFC at the Third Affiliated Hospital of Sun Yat-Sen University(2020G2RPYQN11,China)+3 种基金China International Medical Foundation(2018-N-01)the Science and Technology Plan Project of Guangzhou City(2024A03J0002,China)Key Area R&D Program of Guangdong Province(2019B020227003,China)Sci-Tech Research Development Program of Guangzhou City(202201020589,China).
文摘Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)protect against diabetic cardiovascular diseases and nephropathy.However,their activity in diabetic retinopathy(DR)remains unclear.Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications,suggesting their advantage in DR treatment.By single-cell RNA-sequencing analysis and immunostaining,we observed a high expression of GLP-1R in retinal endothelial cells,which was down-regulated under diabetic conditions.Treatment of GLP-1 RAs significantly restored the receptor expression,resulting in an improvement in retinal degeneration,vascular tortuosity,avascular vessels,and vascular integrity in diabetic mice.GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs.Additionally,the treatment attenuated STING signaling activation in retinal endothelial cells,which is typically activated by leaked mitochondrial DNA.Expression of STING mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes.Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling.This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.