Alternative splicing(AS)is an important approach for pathogens and hosts to remodel transcriptome.However,tuberculosis(TB)-related AS has not been sufficiently explored.Here we presented the first landscape of TB-rela...Alternative splicing(AS)is an important approach for pathogens and hosts to remodel transcriptome.However,tuberculosis(TB)-related AS has not been sufficiently explored.Here we presented the first landscape of TB-related AS by long-read sequencing,and screened four AS events(S100A8-intron1-retention intron,RPS20-exon1-alternaitve promoter,KIF13B-exon4-skipping exon(SE)and UBE2B-exon7-SE)as potential biomarkers in an in-house cohort-1.The validations in an in-house cohort-2(2274 samples)and public datasets(1557 samples)indicated that the latter three AS events are potential promising biomarkers for TB diagnosis,but not for TB progression and prognosis.The excellent performance of classifiers further underscored the diagnostic value of these three biomarkers.Subgroup analyses indicated that UBE2B-exon7-SE splicing was not affected by confounding factors and thus had relatively stable performance.The splicing of UBE2B-exon7-SE can be changed by heat-killed mycobacterium tuberculosis through inhibiting SRSF1 expression.After heat-killed mycobacterium tuberculosis stimulation,231 ubiquitination proteins in macrophages were differentially expressed,and most of them are apoptosis-related proteins.Taken together,we depicted a global TB-associated splicing profile,developed TB-related AS biomarkers,demonstrated an optimal application scope of target biomarkers and preliminarily elucidated mycobacterium tuberculosis-host interaction from the perspective of splicing,offering a novel insight into the pathophysiology of TB.展开更多
基金Thanks to Xuan Chen at West China Hospital of Stomatology,Sichuan University for providing THP-1 cell line.Thanks to Xiaohuan Su at Core Facilities of West China Hospital for cell line identification.Thanks to Sisi Wu,Jinkui Pi,and Yufei Cheng at Core Facilities of West China Hospital for their help on capturing fluorescence signal by using confocal laser scanning microscope(Leica).Thanks to Dr.Li Yu at Tsinghua University,and Chengqi Yi at Peking University for their advices on writing.This work was funded by the National Science&Technology Pillar Program during the 13th Five-year Plan Period[Grant number:2018ZX10715003]National Natural Science Foundation of China[Grant number:82272416,Grant number:U20A20394].
文摘Alternative splicing(AS)is an important approach for pathogens and hosts to remodel transcriptome.However,tuberculosis(TB)-related AS has not been sufficiently explored.Here we presented the first landscape of TB-related AS by long-read sequencing,and screened four AS events(S100A8-intron1-retention intron,RPS20-exon1-alternaitve promoter,KIF13B-exon4-skipping exon(SE)and UBE2B-exon7-SE)as potential biomarkers in an in-house cohort-1.The validations in an in-house cohort-2(2274 samples)and public datasets(1557 samples)indicated that the latter three AS events are potential promising biomarkers for TB diagnosis,but not for TB progression and prognosis.The excellent performance of classifiers further underscored the diagnostic value of these three biomarkers.Subgroup analyses indicated that UBE2B-exon7-SE splicing was not affected by confounding factors and thus had relatively stable performance.The splicing of UBE2B-exon7-SE can be changed by heat-killed mycobacterium tuberculosis through inhibiting SRSF1 expression.After heat-killed mycobacterium tuberculosis stimulation,231 ubiquitination proteins in macrophages were differentially expressed,and most of them are apoptosis-related proteins.Taken together,we depicted a global TB-associated splicing profile,developed TB-related AS biomarkers,demonstrated an optimal application scope of target biomarkers and preliminarily elucidated mycobacterium tuberculosis-host interaction from the perspective of splicing,offering a novel insight into the pathophysiology of TB.
