title: Alternative polyadenylation in glioblastoma multiforme and changes in predicted RNA binding protein profiles.
abstract: Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM.
authors: Systems Biology Division, Zhejiang-California International NanoSystems Institute, Zhejiang University, Hangzhou, China.
authors: Jiaofang
authors: J
authors: Shao
authors: Jing
authors: J
authors: Zhang
authors: Zengming
authors: Z
authors: Zhang
authors: Huawei
authors: H
authors: Jiang
authors: Xiaoyan
authors: X
authors: Lou
authors: Bingding
authors: B
authors: Huang
authors: Gregory
authors: G
authors: Foltz
authors: Qing
authors: Q
authors: Lan
authors: Qiang
authors: Q
authors: Huang
authors: Biaoyang
authors: B
authors: Lin
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D030561:Databases, Nucleic Acid; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D026723:Polyadenylation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012984:Software
chemical_list: C113285:HSBP1 protein, human; D006360:Heat-Shock Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; D009363:Neoplasm Proteins; C491239:PHC1 protein, human; D012322:RNA Precursors; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D063150:Polycomb Repressive Complex 1