PMID- 26216192 OWN - NLM STAT- MEDLINE DCOM- 20160606 LR - 20210513 IS - 1535-3907 (Electronic) IS - 1535-3893 (Print) IS - 1535-3893 (Linking) VI - 14 IP - 9 DP - 2015 Sep 4 TI - Functional Networks of Highest-Connected Splice Isoforms: From The Chromosome 17 Human Proteome Project. PG - 3484-91 LID - 10.1021/acs.jproteome.5b00494 [doi] AB - Alternative splicing allows a single gene to produce multiple transcript-level splice isoforms from which the translated proteins may show differences in their expression and function. Identifying the major functional or canonical isoform is important for understanding gene and protein functions. Identification and characterization of splice isoforms is a stated goal of the HUPO Human Proteome Project and of neXtProt. Multiple efforts have catalogued splice isoforms as "dominant", "principal", or "major" isoforms based on expression or evolutionary traits. In contrast, we recently proposed highest connected isoforms (HCIs) as a new class of canonical isoforms that have the strongest interactions in a functional network and revealed their significantly higher (differential) transcript-level expression compared to nonhighest connected isoforms (NCIs) regardless of tissues/cell lines in the mouse. HCIs and their expression behavior in the human remain unexplored. Here we identified HCIs for 6157 multi-isoform genes using a human isoform network that we constructed by integrating a large compendium of heterogeneous genomic data. We present examples for pairs of transcript isoforms of ABCC3, RBM34, ERBB2, and ANXA7. We found that functional networks of isoforms of the same gene can show large differences. Interestingly, differential expression between HCIs and NCIs was also observed in the human on an independent set of 940 RNA-seq samples across multiple tissues, including heart, kidney, and liver. Using proteomic data from normal human retina and placenta, we showed that HCIs are a promising indicator of expressed protein isoforms exemplified by NUDFB6 and M6PR. Furthermore, we found that a significant percentage (20%, p = 0.0003) of human and mouse HCIs are homologues, suggesting their conservation between species. Our identified HCIs expand the repertoire of canonical isoforms and are expected to facilitate studying main protein products, understanding gene regulation, and possibly evolution. The network is available through our web server as a rich resource for investigating isoform functional relationships (http://guanlab.ccmb.med.umich.edu/hisonet). All MS/MS data were available at ProteomeXchange Web site (http://www.proteomexchange.org) through their identifiers (retina: PXD001242, placenta: PXD000754). FAU - Li, Hong-Dong AU - Li HD AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Menon, Rajasree AU - Menon R AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Govindarajoo, Brandon AU - Govindarajoo B AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Panwar, Bharat AU - Panwar B AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Zhang, Yang AU - Zhang Y AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Omenn, Gilbert S AU - Omenn GS AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. FAU - Guan, Yuanfang AU - Guan Y AD - Department of Computational Medicine and Bioinformatics, double daggerDepartment of Internal Medicine, section signDepartment of Human Genetics and School of Public Health, parallelDepartment of Electrical Engineering and Computer Science University of Michigan , Ann Arbor, Michigan 48109, United States. LA - eng GR - U54ES017885/ES/NIEHS NIH HHS/United States GR - R21 NS082212/NS/NINDS NIH HHS/United States GR - R25 GM086262/GM/NIGMS NIH HHS/United States GR - R35 GM133346/GM/NIGMS NIH HHS/United States GR - P30 ES017885/ES/NIEHS NIH HHS/United States GR - 1R21NS082212-01/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Validation Study DEP - 20150811 PL - United States TA - J Proteome Res JT - Journal of proteome research JID - 101128775 RN - 0 (Protein Isoforms) RN - 0 (Proteins) RN - 0 (Proteome) RN - 0 (RNA, Messenger) SB - IM MH - *Alternative Splicing MH - Animals MH - *Chromosomes, Human, Pair 17 MH - Humans MH - Mice MH - Protein Isoforms/chemistry/*genetics MH - Proteins/chemistry/*genetics MH - *Proteome MH - RNA, Messenger/genetics MH - Sequence Analysis, RNA PMC - PMC4993635 MID - NIHMS784164 OTO - NOTNLM OT - alternative splicing OT - canonical isoforms OT - highest connected isoforms OT - isoform networks EDAT- 2015/07/29 06:00 MHDA- 2016/06/09 06:00 PMCR- 2016/09/04 CRDT- 2015/07/29 06:00 PHST- 2015/07/29 06:00 [entrez] PHST- 2015/07/29 06:00 [pubmed] PHST- 2016/06/09 06:00 [medline] PHST- 2016/09/04 00:00 [pmc-release] AID - 10.1021/acs.jproteome.5b00494 [doi] PST - ppublish SO - J Proteome Res. 2015 Sep 4;14(9):3484-91. doi: 10.1021/acs.jproteome.5b00494. Epub 2015 Aug 11.