Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation

Abstract

Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs. Our bioinformatic analyses of transcriptomic and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control. IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes. Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content. IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway. In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis. Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation.

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

“…Muscleblind-like protein 1 (MBNL1) is highly expressed in cardiac and skeletal muscles (52) and is a known regulator of mRNA splicing in these tissues (53,54). Intron retention has emerged as a widespread mechanism to regulate gene expression in different cell and tissue types as well as during stem cell differentiation (42,55,56). The finding that a retained intron at the 5′-UTR of Yy2 mRNA controls its translation underscores the intricate interplay between alternative splicing and translational control (57, 58).…”

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…We hypothesized that direct mRNA targets arising from splicing dysregulation would be less likely to belong to specific biological functions and would be structurally similar, whereas indirect targets might fall within particular pathways and impact gene expression as a result of activation of a developmental process or stress response (32)(33)(34)(35). Analysis of splice site strength showed that introns with greater degrees of retention had weaker 5′ and 3′ splice sites, as determined by consensus to canonical 5′ and 3′ splice site sequences (36), and retained introns were significantly higher in GC content compared with expression-and length-matched control introns ( Fig.…”

The Y Chromosome Modulates Splicing and Sex-Biased Intron Retention Rates in Drosophila

“…Because of this, mRNAs generated through IR events could be viewed as failures of the splicing process and void of biological function (JAILLON et al 2008;ROY AND IRIMIA 2008). However, recent studies suggested that IR events are involved in multiple cellular and physiological processes, including hematogenesis (WONG et al 2013;EDWARDS et al 2016;PIMENTEL et al 2016), T cell activation (NI et al 2016), neuronal differentiation (BRAUNSCHWEIG et al 2014), and carcinogenesis (DVINGE AND BRADLEY 2015;JUNG et al 2015). Despite these advances, questions remain regarding the extent to which introns are differentially retained between sexes and how sex-biased IR rates are regulated.…”

“…Intron retention (IR) is a type of AS event in which one or more introns are retained in the mRNA molecule. IR is the dominant AS type in Drosophila (GRAVELEY et al 2011) and affects about half of all introns in mammals (WONG et al 2013;BRAUNSCHWEIG et al 2014;EDWARDS et al 2016;PIMENTEL et al 2016). The "anomalous" mRNA generated by the retention of an intron may contain a premature termination codon (PTC) (JAILLON et al 2008), which can sometimes result in the degradation of the mRNA by the nonsense-mediated mRNA decay (NMD) pathway.…”