Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases.
Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases.
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DOI：
10.1038/s41598-018-29086-2
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发表时间：
2018-07-19
影响因子：
4.6
通讯作者：
Hannenhalli S
中科院分区：
文献类型：
--
作者：
Wang K;Wu D;Zhang H;Das A;Basu M;Malin J;Cao K;Hannenhalli S
选择性剪接在多个生物学尺度上促进表型多样性，其失调与人类衰老和年龄相关疾病有关。剪接的跨组织变异性进一步使其与年龄相关表型的联系复杂化，阐明这些联系需要跨多个组织的年龄相关剪接变化的综合图谱。在这里，我们通过分析544个个体的48个组织中的约8500个RNA测序样本来生成这样的地图。采用严格的模型控制多种混杂因素，我们确定了49,869个组织特异性的7种不同类型的年龄相关剪接事件。我们发现，全基因组剪接谱是一个更好的预测生物学年龄比基因和转录表达谱，此外，年龄相关的剪接提供了额外的独立贡献与年龄相关的复杂疾病。我们发现，年龄相关的剪接的变化可以解释，在一定程度上，伴随着年龄相关的变化的上游剪接因子。最后，我们表明，我们的剪接为基础的模型的年龄可以成功地预测8的10对纵向数据，以及在2组细胞传代数据的细胞的相对年龄。我们的研究首次系统地研究了组织中与年龄相关的剪接变化，并进一步加强了与年龄相关的剪接和年龄相关疾病之间的联系。
Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases.
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影响因子：
4.4
作者：
Chaves DF;Carvalho PC;Lima DB;Nicastro H;Lorenzeti FM;Siqueira-Filho M;Hirabara SM;Alves PH;Moresco JJ;Yates JR 3rd;Lancha AH Jr
通讯作者：
Lancha AH Jr
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
3.5
作者：
Berdyyeva, TK;Woodworth, CD;Sokolov, I
通讯作者：
Sokolov, I
影响因子：
4.5
作者：
Kawakami, Kyojiro;Nakamura, Akihiro;Takahashi, Ryoya
通讯作者：
Takahashi, Ryoya
影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY