Novel roles for small non-coding RNA within the endogenous spliceosome in alternative splicing regulation

Splicing and alternative splicing (AS), which occur within the endogenous spliceosome, play major roles in regulating gene expression, and defects in them are involved in numerous human diseases including cancer. Although the mechanism of the splicing reaction is well understood, the regulation of AS remains to be elucidated. Furthermore, the number of known splicing factors is order-of-magnitude lower than that of known transcription factors, suggesting yet unidentified splicing factors. A group of essential regulatory factors in gene expression are small non-coding RNAs (sncRNAs): e.g. microRNA, mainly known for their inhibitory role in translation in the cytoplasm; and small nucleolar RNA, known for their role in modifying non-coding RNA in the nucleolus. Here I present a novel functional aspect of sncRNAs found within the endogenous spliceosome. RNA sequencing of sncRNAs within the endogenous spliceosome revealed a large collection of them within it, among them numerous known cancer-associated sncRNAs. Importantly, changes in the levels and types of spliceosomal sncRNAs were observed in disease. Several of the spliceosomal sncRNAs are found assembled in non-canonical complexes, and acting through different base pairing than their canonical ones. Thus, spliceosomal sncRNAs can potentially target different RNAs than their canonical complexes. Examples are spliceosomal sncRNAs regulating AS, and others regulating gene expression. Notably, recent findings demonstrate a sncRNA acting in a quality control mechanism of AS and identify factors associated with it. These studies highlight novel roles for sncRNAs within the endogenous spliceosome as regulators of gene expression in health and disease.