Differential fates of introns in gene expression due to global alternative splicing

Anjani Kumari,John David Brook,Piotr Kozlowski,Saam Sedehizadeh,Marzena Wojciechowska

doi:10.1007/s00439-021-02409-6

Abstract

The discovery of introns over four decades ago revealed a new vision of genes and their interrupted arrangement. Throughout the years, it has appeared that introns play essential roles in the regulation of gene expression. Unique processing of excised introns through the formation of lariats suggests a widespread role for these molecules in the structure and function of cells. In addition to rapid destruction, these lariats may linger on in the nucleus or may even be exported to the cytoplasm, where they remain stable circular RNAs (circRNAs). Alternative splicing (AS) is a source of diversity in mature transcripts harboring retained introns (RI-mRNAs). Such RNAs may contain one or more entire retained intron(s) (RIs), but they may also have intron fragments resulting from sequential excision of smaller subfragments via recursive splicing (RS), which is characteristic of long introns. There are many potential fates of RI-mRNAs, including their downregulation via nuclear and cytoplasmic surveillance systems and the generation of new protein isoforms with potentially different functions. Various reports have linked the presence of such unprocessed transcripts in mammals to important roles in normal development and in disease-related conditions. In certain human neurological-neuromuscular disorders, including myotonic dystrophy type 2 (DM2), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Duchenne muscular dystrophy (DMD), peculiar processing of long introns has been identified and is associated with their pathogenic effects. In this review, we discuss different mechanisms involved in the processing of introns during AS and the functions of these large sections of the genome in our biology.

Highlights

Introns, as well as their splicing and retention were discovered in 1977 as a result of an interesting observation that the mRNA used to code for proteins was almost always shorter than the DNA from which it had been transcribed (Berget and Sharp 1977; Chow et al 1977)
The original publications described the discovery in adenovirus mRNAs, but it soon became clear that this mechanism was not solely a viral phenomenon since introns were found in cellular genes
Intronic sequences that account for over 20% of the human genome provide a source of noncoding RNAs, and their processing and biological functions have been of particular interest in recent years (Zhang et al 2013)

Summary

Introduction

As well as their splicing and retention were discovered in 1977 as a result of an interesting observation that the mRNA used to code for proteins was almost always shorter than the DNA from which it had been transcribed (Berget and Sharp 1977; Chow et al 1977). The original publications described the discovery in adenovirus mRNAs, but it soon became clear that this mechanism was not solely a viral phenomenon since introns were found in cellular genes

Present Address

Concluding remarks

Findings

Methods