Long non-coding RNAs(lncRNAs)play a significant role in maintaining tissue morphology and functions,and their precise regulatory effectiveness is closely related to expression patterns.However,the spatial expression p...Long non-coding RNAs(lncRNAs)play a significant role in maintaining tissue morphology and functions,and their precise regulatory effectiveness is closely related to expression patterns.However,the spatial expression patterns of lncRNAs in humans are poorly characterized.Here,we constructed five comprehensive transcriptomic atlases of human lncRNAs covering thousands of major tissue samples in normal and disease states.The lncRNA transcriptomes exhibited high consistency within the same tissues across resources,and even higher complexity in specialized tissues.Tissue-elevated(TE)lncRNAs were identified in each resource and robust TE lncRNAs were refined by integrative analysis.We detected 1 to 4684 robust TE lncRNAs across tissues;the highest number was in testis tissue,followed by brain tissue.Functional analyses of TE lncRNAs indicated important roles in corresponding tissue-related pathways.Moreover,we found that the expression features of robust TE lncRNAs made them be effective biomarkers to distinguish tissues;TE lncRNAs also tended to be associated with cancer,and exhibited differential expression or were correlated with patient survival.In summary,spatial classification of lncRNAs is the starting point for elucidating the function of lncRNAs in both maintenance of tissue morphology and progress of tissue-constricted diseases.展开更多
Genome editing through adeno-associated viral(AAV) vectors is a promising gene therapy strategy for various diseases,especially genetic disorders. However, homologous recombination(HR) efficiency is extremely low in a...Genome editing through adeno-associated viral(AAV) vectors is a promising gene therapy strategy for various diseases,especially genetic disorders. However, homologous recombination(HR) efficiency is extremely low in adult animal models. We assumed that increasing AAV transduction efficiency could increase genome editing activity, especially HR efficiency, for in vivo gene therapy. Firstly, a mouse phenylketonuria(PKU) model carrying a pathogenic R408W mutation in phenylalanine hydroxylase(Pah) was generated. Through co-delivery of the general AAV receptor(AAVR), we found that AAVR could dramatically increase AAV transduction efficiency in vitro and in vivo. Furthermore, co-delivery of SaCas9/sgRNA/donor templates with AAVR via AAV8 vectors increased indel rate over 2-fold and HR rate over 15-fold for the correction of the single mutation in Pah;mice. Moreover, AAVR co-injection successfully increased the site-specific insertion rate of a 1.4 kb Pah cDNA by 11-fold, bringing the HR rate up to 7.3% without detectable global off-target effects. Insertion of Pah cDNA significantly decreased the Phe level and ameliorated PKU symptoms. This study demonstrates a novel strategy to dramatically increase AAV transduction which substantially enhanced in vivo genome editing efficiency in adult animal models, showing clinical potential for both conventional and genome editing-based gene therapy.展开更多
Dear Editor,Diffuse large B-cell lymphoma(DLBCL)is the most common and aggressive subtype of non-Hodgkin lymphoma(NHL),accounting for about 40%of all NHL cases[1].Lacking symptoms at early time and efficient therapeut...Dear Editor,Diffuse large B-cell lymphoma(DLBCL)is the most common and aggressive subtype of non-Hodgkin lymphoma(NHL),accounting for about 40%of all NHL cases[1].Lacking symptoms at early time and efficient therapeutic methods made DLBCL one of the most life-threatening types of hematopoietic malignancy[2,3].Therefore,identifying novel therapeutic biomarker for early detection and prognosis prediction is urgently needed.展开更多
基金This work was supported by the National Natural Science Foundation of China(Nos.31970646,32060152,32070673,and 32170676)the Hainan Province Science and Technology Special Fund(No.ZDYF2021SHFZ051)+2 种基金the Harbin Medical University Marshal Initiative Funding(No.HMUMIF-21024)the Marshal Initiative Funding of Hainan Medical University(No.JBGS202103)the Heilongjiang Touyan Innovation Team Program.
文摘Long non-coding RNAs(lncRNAs)play a significant role in maintaining tissue morphology and functions,and their precise regulatory effectiveness is closely related to expression patterns.However,the spatial expression patterns of lncRNAs in humans are poorly characterized.Here,we constructed five comprehensive transcriptomic atlases of human lncRNAs covering thousands of major tissue samples in normal and disease states.The lncRNA transcriptomes exhibited high consistency within the same tissues across resources,and even higher complexity in specialized tissues.Tissue-elevated(TE)lncRNAs were identified in each resource and robust TE lncRNAs were refined by integrative analysis.We detected 1 to 4684 robust TE lncRNAs across tissues;the highest number was in testis tissue,followed by brain tissue.Functional analyses of TE lncRNAs indicated important roles in corresponding tissue-related pathways.Moreover,we found that the expression features of robust TE lncRNAs made them be effective biomarkers to distinguish tissues;TE lncRNAs also tended to be associated with cancer,and exhibited differential expression or were correlated with patient survival.In summary,spatial classification of lncRNAs is the starting point for elucidating the function of lncRNAs in both maintenance of tissue morphology and progress of tissue-constricted diseases.
基金partially supported by grants from the National Key R&D Program of China (2019YFA0110802)the National Natural Science Foundation of China (81670470 and 81873685)+2 种基金grants from the Shanghai Municipal Commission for Science and Technology (18411953500 and 20140900201)a grant from the Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-05-E00054)the Fundamental Research Funds for the Central Universities
文摘Genome editing through adeno-associated viral(AAV) vectors is a promising gene therapy strategy for various diseases,especially genetic disorders. However, homologous recombination(HR) efficiency is extremely low in adult animal models. We assumed that increasing AAV transduction efficiency could increase genome editing activity, especially HR efficiency, for in vivo gene therapy. Firstly, a mouse phenylketonuria(PKU) model carrying a pathogenic R408W mutation in phenylalanine hydroxylase(Pah) was generated. Through co-delivery of the general AAV receptor(AAVR), we found that AAVR could dramatically increase AAV transduction efficiency in vitro and in vivo. Furthermore, co-delivery of SaCas9/sgRNA/donor templates with AAVR via AAV8 vectors increased indel rate over 2-fold and HR rate over 15-fold for the correction of the single mutation in Pah;mice. Moreover, AAVR co-injection successfully increased the site-specific insertion rate of a 1.4 kb Pah cDNA by 11-fold, bringing the HR rate up to 7.3% without detectable global off-target effects. Insertion of Pah cDNA significantly decreased the Phe level and ameliorated PKU symptoms. This study demonstrates a novel strategy to dramatically increase AAV transduction which substantially enhanced in vivo genome editing efficiency in adult animal models, showing clinical potential for both conventional and genome editing-based gene therapy.
基金This work was supported by the National Natural Science Foundation of China(81802424).
文摘Dear Editor,Diffuse large B-cell lymphoma(DLBCL)is the most common and aggressive subtype of non-Hodgkin lymphoma(NHL),accounting for about 40%of all NHL cases[1].Lacking symptoms at early time and efficient therapeutic methods made DLBCL one of the most life-threatening types of hematopoietic malignancy[2,3].Therefore,identifying novel therapeutic biomarker for early detection and prognosis prediction is urgently needed.
