Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,K...Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability.Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and memory.Here,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory deficits.To test this,we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre.We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in mice.These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.展开更多
Background: Preadipocyte differentiation plays a critical role in subcutaneous fat deposition in pigs.However,the roles of different RNAs,such as messenger RNAs(mRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(c...Background: Preadipocyte differentiation plays a critical role in subcutaneous fat deposition in pigs.However,the roles of different RNAs,such as messenger RNAs(mRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs) in the differentiation process of subcutaneous preadipocytes,are still largely unclear.In the present study,a transcriptome analysis,including the analysis of mRNAs,lncRNAs,and circRNAs,during different differentiation stages,namely,day 0(D0),day 2(D2),day 4(D4),and day 8(D8),of subcutaneous preadipocytes from Chinese Erhualian pigs was performed.Results: A total of 1554,470,1344,1777,and 676 differentially expressed(DE) mRNAs,112,58,95,136,and 93 DE lncRNAs,and 902,787,710,932,and 850 DE circRNAs were identified between D2 and D0,between D4 and D2,between D8 and D4,between D4 and D0,and between D8 and D0,respectively.Furthermore,functional enrichment analysis showed that the common DE mRNAs during the entire differentiation process were mainly involved in lipid metabolic and cell differentiation processes.Additionally,co-expression network analysis identified the potential lncRNAs related to adipogenesis,e.g.,MSTRG.131380 and MSTRG.62128.Conclusions: Our study provides new insights of the expression changes of RNAs during adipogenic differentiation,which might contribute to the phenotype of subcutaneous adipogenesis.These results greatly improve our understanding of the molecular mechanisms regulating subcutaneous fat deposition in pigs.展开更多
Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derive...Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derived from new systems biology theory, the dynamic network biomarker (DNB) method is designed to quantitatively identify the tipping point of a drastic system transition and can theoretically identify DNB genes that play key roles in acquiring drug resistance.We analyzed time-course mRNA sequence data generated from the tamoxifen-treated estrogen receptor (ER)-positive MCF-7 cell line, and identified the tipping point of endocrine resistance with its leading molecules.The results show that there is interplay between gene mutations and DNB genes, in which the accumulated mutations eventually affect the DNB genes that subsequently cause the change of transcriptional landscape, enabling full-blown drug resistance. Survival analyses based on clinical datasets validated that the DNB genes were associated with the poor survival of breast cancer patients.The results provided the detection for the pre-resistance state or early signs of endocrine resistance.Our predictive method may greatly benefit the scheduling of treatments for complex diseases in which patients are exposed to considerably different drugs and may become drug resistant.展开更多
Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(...Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(BSJ)sites.Therefore,examination of global circ RNA expression from RNA-seq datasets generally relies on the detection of RNA-seq fragments spanning BSJ sites,which is different from the quantification of linear RNA expression by normalized RNA-seq fragments mapped to whole gene bodies.Thus,direct comparison of circular and linear RNA expression from the same gene loci in a genome-wide manner has remained challenging.Here,we update the previously-reported CIRCexplorer pipeline to version 3 for circular and linear RNA expression analysis from ribosomal-RNA depleted RNA-seq(CIRCexplorer3-CLEAR).A new quantitation parameter,fragments per billion mapped bases(FPB),is applied to evaluate circular and linear RNA expression individually by fragments mapped to circ RNA-specific BSJ sites or to linear RNA-specific splicing junction(SJ)sites.Comparison of circular and linear RNA expression levels is directly achieved by dividing FPBcircby FPBlinearto generate a CIRCscore,which indicates the relative circ RNA expression level using linear RNA expression level as the background.Highlyexpressed circ RNAs with low cognate linear RNA expression background can be readily identified by CIRCexplorer3-CLEAR for further investigation.CIRCexplorer3-CLEAR is publically available at https://github.com/Yang Lab/CLEAR.展开更多
基金supported by the National Natural Science Foundation of China,No. 81771228Shanghai Association of Science and Technology,Nos. 22WZ2501700 and 23WZ2504500 (all to LY)
文摘Bromodomain and plant homeodomain(PHD)finger containing protein 1(Brpf1)is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase(KAT)6A/6B/7.Brpf1,KAT6A,and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability.Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain,especially the hippocampus,which has essential roles in learning and memory.Here,we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons,and that its deficiency leads to learning and memory deficits.To test this,we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre.We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1,Slc16a7,Robo3,and Rho,which are related to neural development,synapse function,and memory,thereby damaging spatial and fear memory in mice.These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.
基金supported by the National Transgenic Project of China(2018ZX0800928B)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2015BAD03B01)the National Natural Science Foundation of China(31501930)
文摘Background: Preadipocyte differentiation plays a critical role in subcutaneous fat deposition in pigs.However,the roles of different RNAs,such as messenger RNAs(mRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs) in the differentiation process of subcutaneous preadipocytes,are still largely unclear.In the present study,a transcriptome analysis,including the analysis of mRNAs,lncRNAs,and circRNAs,during different differentiation stages,namely,day 0(D0),day 2(D2),day 4(D4),and day 8(D8),of subcutaneous preadipocytes from Chinese Erhualian pigs was performed.Results: A total of 1554,470,1344,1777,and 676 differentially expressed(DE) mRNAs,112,58,95,136,and 93 DE lncRNAs,and 902,787,710,932,and 850 DE circRNAs were identified between D2 and D0,between D4 and D2,between D8 and D4,between D4 and D0,and between D8 and D0,respectively.Furthermore,functional enrichment analysis showed that the common DE mRNAs during the entire differentiation process were mainly involved in lipid metabolic and cell differentiation processes.Additionally,co-expression network analysis identified the potential lncRNAs related to adipogenesis,e.g.,MSTRG.131380 and MSTRG.62128.Conclusions: Our study provides new insights of the expression changes of RNAs during adipogenic differentiation,which might contribute to the phenotype of subcutaneous adipogenesis.These results greatly improve our understanding of the molecular mechanisms regulating subcutaneous fat deposition in pigs.
基金This work was supported by grants from the National Key R&D Program of China (2017YFA0505500)Strategic Priority Research Program of the Chinese Academy of Sciences (XDBl3040700)+6 种基金the National Natural Science Foundation of China (11771152,91529303,31771476,31571363,31771469,91530320,61134013,81573023,81501203,and 11326035)Pearl River Science and Technology Nova Program of Guangzhou (201610010029)FISRT,Aihara Innovative Mathematical Modeling Project from Cabinet Office,JapanFundamental Research Funds for the Central Universities (2017ZD095)JSPS KAKENHI (15H05707)Grant-in-Aid for Scientific Research on Innovative Areas (3901) and SPS KAKENHI (15KT0084,17H06299,17H06302,and 18H04031)RIKEN Epigenome and Single Cell Project Grants to M.O.-H.This work was performed in part under the International Cooperative Research Program of Institute for Protein Research,Osaka University (ICRa-17-01 to L.C.and M.O.-H.).
文摘Acquired drug resistance is the major reason why patients fail to respond to cancer therapies.It is a challenging task to deter.mine the tipping point of endocrine resistance and detect the associated molecules.Derived from new systems biology theory, the dynamic network biomarker (DNB) method is designed to quantitatively identify the tipping point of a drastic system transition and can theoretically identify DNB genes that play key roles in acquiring drug resistance.We analyzed time-course mRNA sequence data generated from the tamoxifen-treated estrogen receptor (ER)-positive MCF-7 cell line, and identified the tipping point of endocrine resistance with its leading molecules.The results show that there is interplay between gene mutations and DNB genes, in which the accumulated mutations eventually affect the DNB genes that subsequently cause the change of transcriptional landscape, enabling full-blown drug resistance. Survival analyses based on clinical datasets validated that the DNB genes were associated with the poor survival of breast cancer patients.The results provided the detection for the pre-resistance state or early signs of endocrine resistance.Our predictive method may greatly benefit the scheduling of treatments for complex diseases in which patients are exposed to considerably different drugs and may become drug resistant.
基金the Strategic Priority Research Program of Chinese Academy of Sciences,China(Grant No.XDB19020104)the National Natural Science Foundation of China(Grant Nos.31730111,31925011,and 91940306)the Howard Hughes Medical Institute International Program,the United States(Grant No.55008728).
文摘Sequences of circular RNAs(circ RNAs)produced from back-splicing of exon(s)completely overlap with those from cognate linear RNAs transcribed from the same gene loci with the exception of their back-splicing junction(BSJ)sites.Therefore,examination of global circ RNA expression from RNA-seq datasets generally relies on the detection of RNA-seq fragments spanning BSJ sites,which is different from the quantification of linear RNA expression by normalized RNA-seq fragments mapped to whole gene bodies.Thus,direct comparison of circular and linear RNA expression from the same gene loci in a genome-wide manner has remained challenging.Here,we update the previously-reported CIRCexplorer pipeline to version 3 for circular and linear RNA expression analysis from ribosomal-RNA depleted RNA-seq(CIRCexplorer3-CLEAR).A new quantitation parameter,fragments per billion mapped bases(FPB),is applied to evaluate circular and linear RNA expression individually by fragments mapped to circ RNA-specific BSJ sites or to linear RNA-specific splicing junction(SJ)sites.Comparison of circular and linear RNA expression levels is directly achieved by dividing FPBcircby FPBlinearto generate a CIRCscore,which indicates the relative circ RNA expression level using linear RNA expression level as the background.Highlyexpressed circ RNAs with low cognate linear RNA expression background can be readily identified by CIRCexplorer3-CLEAR for further investigation.CIRCexplorer3-CLEAR is publically available at https://github.com/Yang Lab/CLEAR.
