Widespread splicing changes in human brain development and aging

Molecular Systems Biology

Pavel Mazin³  Jieyi Xiong³  Xiling Liu³  Zheng Yan³  Xiaoyu Zhang³  Mingshuang Li³  Liu He³  Mehmet Somel³  Yuan Yuan³  Yi-Ping Phoebe Chen⁶  Na Li²  Yuhui Hu²  Ning Fu¹  Zhibin Ning¹  Rong Zeng¹  Hongyi Yang⁴  Wei Chen²  Mikhail Gelfand⁵ 

[1] Key Laboratory of Systems Biology, Chinese Academy of Sciences, Shanghai, China;Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin-Buch, Germany;Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China;College of Life Science, Northeast Forestry University, Harbin, China;Department of Bioengineering and Bioinformatics, Moscow State University, Moscow, Russia;Department of Computer Science and Computer Engineering, La Trobe University, Melbourne, Victoria, Australia

关键词: alternative splicing;    brain;    development;    human;    RNA‐seq;   

DOI  :  10.1038/msb.2012.67

来源: Wiley

【 摘 要 】

Abstract

While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high-throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA-seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense-mediated decay in infants and elderly.

Synopsis

Human brain transcriptome analysis revealed widespread age-related splicing changes in the prefrontal cortex and cerebellum. While most of the splicing changes take place in development, approximately one-third of them extends into aging.

• More than one-third of genes expressed in the human brain change splicing with age.
• Approximately 30% of observed splicing changes occur in aging.
• Age-related splicing patterns are largely conserved between the human and macaque brains.
• High frequency of intron retention events suggests the role of nonsense-mediated decay in age-related gene expression regulation.

【 授权许可】

CC BY-NC-SA   
Copyright © 2013 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.