Regulation of alternative splicing by the circadian clock and food related cues

Abstract

BackgroundThe circadian clock orchestrates daily rhythms in metabolism, physiology and behaviour that allow organisms to anticipate regular changes in their environment, increasing their adaptation. Such circadian phenotypes are underpinned by daily rhythms in gene expression. Little is known, however, about the contribution of post-transcriptional processes, particularly alternative splicing.ResultsUsing Affymetrix mouse exon-arrays, we identified exons with circadian alternative splicing in the liver. Validated circadian exons were regulated in a tissue-dependent manner and were present in genes with circadian transcript abundance. Furthermore, an analysis of circadian mutant Vipr2-/- mice revealed the existence of distinct physiological pathways controlling circadian alternative splicing and RNA binding protein expression, with contrasting dependence on Vipr2-mediated physiological signals. This view was corroborated by the analysis of the effect of fasting on circadian alternative splicing. Feeding is an important circadian stimulus, and we found that fasting both modulates hepatic circadian alternative splicing in an exon-dependent manner and changes the temporal relationship with transcript-level expression.ConclusionsThe circadian clock regulates alternative splicing in a manner that is both tissue-dependent and concurrent with circadian transcript abundance. This adds a novel temporal dimension to the regulation of mammalian alternative splicing. Moreover, our results demonstrate that circadian alternative splicing is regulated by the interaction between distinct physiological cues, and illustrates the capability of single genes to integrate circadian signals at different levels of regulation.

Ribosome profiling reveals an important role for translational control in circadian gene expression

“…There are a number of previous reports that link the regulation of multiple post-transcriptional events to the mammalian clock (Gatfield et al 2009;Kojima et al 2010Kojima et al , 2012McGlincy et al 2012;Morf et al 2012). The LSM1 gene showed rhythmic RPF accumulation and an expressed, albeit nonoscillatory, uORF.…”

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

“…Although this process could, in principle, regulate circadian accumulation of many transcripts, surprisingly few works have analyzed the contribution of alternative splicing to mammalian circadian gene expression. In fact, exon arrays have shown that relatively few circadian transcripts (0.4%) are regulated at the splicing level in mouse liver (McGlincy et al 2012), although these transcripts included notable clock components such as Clock and Npas2. Single-gene analysis reported that rhythmic degradation of PER1 is regulated by circadian alternative splicing of the U2AF26 factor (Preussner et al 2014).…”

Considerations for RNA-seq Analysis of Circadian Rhythms

“…To identify CCGs and understand the mechanism of their regulation, microarrays have been used to profile rhythmic gene expression systematically in cyanobacteria, plants, insects, fungi, mice, and cellular models (Atwood et al, 2011;Covington, Maloof, Straume, Kay, & Harmer, 2008;Hughes et al, 2009;Hughes, Hong, et al, 2012;Keegan, Pradhan, Wang, & Allada, 2007;Kornmann, Schaad, Bujard, Takahashi, & Schibler, 2007;McGlincy et al, 2012;Menger et al, 2007;Rund, Hou, Ward, Collins, & Duffield, 2011;Vollmers et al, 2009;Xu, DiAngelo, Hughes, Hogenesch, & Sehgal, 2011). These studies have contributed significantly to our understanding of circadian output in wild-type animals, and over time they have matured into investigations of more focused tissues and cell types (Collins, Kane, Reeves, Akabas, & Blau, 2012;Kula-Eversole et al, 2010).…”