Functional Splicing Network Reveals Extensive Regulatory Potential of the Core Spliceosomal Machinery

TL;DR

This study constructs a network of spliceosomal components revealing extensive regulatory roles of core spliceosomal machinery, highlighting new regulatory mechanisms and potential drug targets in splicing regulation.

Contribution

It systematically analyzes spliceosomal component knockdowns to uncover a regulatory network, emphasizing the regulatory potential of core spliceosomal proteins during assembly.

Findings

Core spliceosomal components have significant regulatory roles.

The network captures known and novel functional associations.

Insights into splicing regulation mechanisms and drug targets.

Abstract

Pre-mRNA splicing relies on the poorly understood dynamic interplay between >150 protein components of the spliceosome. The steps at which splicing can be regulated remain largely unknown. We systematically analyzed the effect of knocking down the components of the splicing machinery on alternative splicing events relevant for cell proliferation and apoptosis and used this information to reconstruct a network of functional interactions. The network accurately captures known physical and functional associations and identifies new ones, revealing remarkable regulatory potential of core spliceosomal components, related to the order and duration of their recruitment during spliceosome assembly. In contrast with standard models of regulation at early steps of splice site recognition, factors involved in catalytic activation of the spliceosome display regulatory properties. The network also sheds light on the antagonism between hnRNP C and U2AF, and on targets of antitumor drugs, and can be widely used to identify mechanisms of splicing regulation.