Intron retention as a component of regulated gene expression programs

Abstract

Intron retention has long been an exemplar of regulated splicing with case studies of individual events serving as models that provided key mechanistic insights into the process of splicing control. In organisms such as plants and budding yeast, intron retention is well understood as a major mechanism of gene expression regulation. In contrast, in mammalian systems, the extent and functional significance of intron retention have, until recently, remained greatly underappreciated. Technical challenges to the global detection and quantitation of transcripts with retained introns have often led to intron retention being overlooked or dismissed as “noise”. Now, however, with the wealth of information available from high-throughput deep sequencing, combined with focused computational and statistical analyses, we are able to distinguish clear intron retention patterns in various physiological and pathological contexts. Several recent studies have demonstrated intron retention as a central component of gene expression programs during normal development as well as in response to stress and disease. Furthermore, these studies revealed various ways in which intron retention regulates protein isoform production, RNA stability and translation efficiency, and rapid induction of expression via post-transcriptional splicing of retained introns. In this review, we highlight critical findings from these transcriptomic studies and discuss commonalties in the patterns prevalent in intron retention networks at the functional and regulatory levels.

Exon definition facilitates reliable control of alternative splicing in the RON proto-oncogene

“…For instance, during granulocyte differentiation, intron retention is enhanced for dozens of genes. Interestingly, this involves a switch from exon to intron definition, as splice factors which favor intron definition complexes are upregulated which promotes the retention of short introns with weak splice sites (24,25). Our work transfers these earlier findings into a continuous and quantitative description of all splice products, and shows that intron retention is an inevitable consequence of the intron definition mechanism.…”

“…This may explain why exon definition dominates for human exons, and raises the question how simple organisms with prevalent intron definition accurately control alternative splicing decisions. Consistently, alternative splicing in S. cerevisiae is largely restricted to the regulated retention of a small number of short introns (25).…”

Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma

“…Notably, an increase in transcripts entering the DI pathway will result in reduced levels of productive coding mRNA. Intron retention has previously been observed to differentiate tumors from matched normal tissue (Dvinge and Bradley, 2015; Jacob and Smith, 2017). While there is extensive data showing that splicing processes are altered in cancer cells, little is known about how to target these processes in cancer patients.…”

Microfluidic isoform sequencing shows widespread splicing coordination in the human transcriptome

“…S5; Lambert et al 2013). In both genes, we observe rare but existing intron retention events, which have attracted considerable interest in recent times (Braunschweig et al 2014;Jacob and Smith 2017). The increased coordination between entirely protein-coding exons prompted us to investigate the involved proteins.…”