IIIDB: a database for isoform-isoform interactions and isoform network modules.

Yu-Ting Tseng,Chun-Chi Liu,Ching-Hsien Chen,Xianghong Jasmine Zhou,Wenyuan Li,Shihua Zhang,Jeremy Jw Chen

doi:10.1186/1471-2164-16-s2-s10

Abstract

BackgroundProtein-protein interactions (PPIs) are key to understanding diverse cellular processes and disease mechanisms. However, current PPI databases only provide low-resolution knowledge of PPIs, in the sense that "proteins" of currently known PPIs generally refer to "genes." It is known that alternative splicing often impacts PPI by either directly affecting protein interacting domains, or by indirectly impacting other domains, which, in turn, impacts the PPI binding. Thus, proteins translated from different isoforms of the same gene can have different interaction partners.ResultsDue to the limitations of current experimental capacities, little data is available for PPIs at the resolution of isoforms, although such high-resolution data is crucial to map pathways and to understand protein functions. In fact, alternative splicing can often change the internal structure of a pathway by rearranging specific PPIs. To fill the gap, we systematically predicted genome-wide isoform-isoform interactions (IIIs) using RNA-seq datasets, domain-domain interaction and PPIs. Furthermore, we constructed an III database (IIIDB) that is a resource for studying PPIs at isoform resolution. To discover functional modules in the III network, we performed III network clustering, and then obtained 1025 isoform modules. To evaluate the module functionality, we performed the GO/pathway enrichment analysis for each isoform module.ConclusionsThe IIIDB provides predictions of human protein-protein interactions at the high resolution of transcript isoforms that can facilitate detailed understanding of protein functions and biological pathways. The web interface allows users to search for IIIs or III network modules. The IIIDB is freely available at http://syslab.nchu.edu.tw/IIIDB.

Highlights

Protein-protein interactions (PPIs) are key to understanding diverse cellular processes and disease mechanisms
To confirm with PPI, given an isoform interactions (IIIs) prediction I1 and I2, we only keep this prediction if the gene symbols of I1 and I2 have PPI in IntAct database
High-confidence and low-confidence prediction of IIIs In the III database (IIIDB), we provided two III prediction sets using the logistic regression model: (a) high-confidence prediction: logit score > 2.575, it resulted in 4,476 IIIs; and (b) low-confidence prediction: logit score > 1.692

Summary

Results

To obtain the isoform annotations in the human genome, we used the NCBI Reference Sequences (RefSeq) mRNAs as transcriptome annotation [15]. A PPI has at least one isoform-isoform interaction It resulted in 54,605 IIIs (Figure 3). To obtain more IIIs for the GSP, we applied the following rule: given a PPI between protein P1 and P2, if both P1 and P2 only have single isoforms we take it as the GSP. It resulted in 11,356 IIIs in the GSP set. Bruey et al reported that Bcl-xL interacts with NALP1 to suppress apoptosis [22] These previous biological studies validated our III prediction of BCL2L1. The IIIDB assigned the RASSF1 isoform A and C into the Mod-162 and the Mod-384, respectively, suggesting a new hypothesis of the isoform-level modules

Conclusions

Background

Methods