Research Paper Volume 10, Issue 6 pp 1489—1505

Regulatory RNA binding proteins contribute to the transcriptome-wide splicing alterations in human cellular senescence

Qiongye Dong 1, 2, , Lei Wei 1, 2, , Michael Q. Zhang 1, 2, 3, 4, , Xiaowo Wang 1, 2, ,

  • 1 Ministry of Education Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Department of Automation, Tsinghua University, Beijing, 100084, China
  • 2 Bioinformatics Division, Beijing National Research Center for Information Science and Technology, Beijing, 100084, China
  • 3 Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China
  • 4 Department of Biological Sciences, Center for Systems Biology, The University of Texas, Richardson, TX 75080, USA

received: May 7, 2018 ; accepted: June 14, 2018 ; published: June 24, 2018 ;

https://doi.org/10.18632/aging.101485
How to Cite

Copyright: Dong et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Dysregulation of mRNA splicing has been observed in certain cellular senescence process. However, the common splicing alterations on the whole transcriptome shared by various types of senescence are poorly understood. In order to systematically identify senescence-associated transcriptomic changes in genome-wide scale, we collected RNA sequencing datasets of different human cell types with a variety of senescence-inducing methods from public databases and performed meta-analysis. First, we discovered that a group of RNA binding proteins were consistently down-regulated in diverse senescent samples and identified 406 senescence-associated common differential splicing events. Then, eight differentially expressed RNA binding proteins were predicted to regulate these senescence-associated splicing alterations through an enrichment analysis of their RNA binding information, including motif scanning and enhanced cross-linking immunoprecipitation data. In addition, we constructed the splicing regulatory modules that might contribute to senescence-associated biological processes. Finally, it was confirmed that knockdown of the predicted senescence-associated potential splicing regulators through shRNAs in HepG2 cell line could result in senescence-like splicing changes. Taken together, our work demonstrated a broad range of common changes in mRNA splicing switches and detected their central regulatory RNA binding proteins during senescence. These findings would help to better understand the coordinating splicing alterations in cellular senescence.

Abbreviations

CS: cellular senescence; AS: alternative splicing; RBP: RNA binding proteins; GO: gene ontology; eCLIP: enhanced crosslinking and immunoprecipitation; SE: skipped exon; A5SS: alternative 5’ splice site; A3SS: alternative 3’ splice site; MXE: mutually exclusive exon; RI: retained intron.