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

ABSTRACT: BACKGROUND:The 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. RESULTS:Using 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. CONCLUSIONS:The 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.

SUBMITTER: McGlincy NJ

PROVIDER: S-EPMC3446320 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

McGlincy Nicholas J NJ Valomon Amandine A Chesham Johanna E JE Maywood Elizabeth S ES Hastings Michael H MH Ule Jernej J

Genome biology 20120621 6

<h4>Background</h4>The 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.<h4>Results</h4>Using Affymetrix mouse exon-arrays, we identified exons with circadian alternat ...[more]

PMID: 22721557

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Project description:BACKGROUND: Recent mapping of eukaryotic transcriptomes and spliceomes using massively parallel RNA sequencing (RNA-seq) has revealed that the extent of alternative splicing has been considerably underestimated. Evidence also suggests that many pre-mRNAs undergo unproductive alternative splicing resulting in incorporation of in-frame premature termination codons (PTCs). The destinies and potential functions of the PTC-harboring mRNAs remain poorly understood. Unproductive alternative splicing in circadian clock genes presents a special case study because the daily oscillations of protein expression levels require rapid and steep adjustments in mRNA levels. RESULTS: We conducted a systematic survey of alternative splicing of plant circadian clock genes using RNA-seq and found that many Arabidopsis thaliana circadian clock-associated genes are alternatively spliced. Results were confirmed using reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR), and/or Sanger sequencing. Intron retention events were frequently observed in mRNAs of the CCA1/LHY-like subfamily of MYB transcription factors. In contrast, the REVEILLE2 (RVE2) transcript was alternatively spliced via inclusion of a "poison cassette exon" (PCE). The PCE type events introducing in-frame PTCs are conserved in some mammalian and plant serine/arginine-rich splicing factors. For some circadian genes such as CCA1 the ratio of the productive isoform (i.e., a representative splice variant encoding the full-length protein) to its PTC counterpart shifted sharply under specific environmental stress conditions. CONCLUSIONS: Our results demonstrate that unproductive alternative splicing is a widespread phenomenon among plant circadian clock genes that frequently generates mRNA isoforms harboring in-frame PTCs. Because LHY and CCA1 are core components of the plant central circadian oscillator, the conservation of alternatively spliced variants between CCA1 and LHY and for CCA1 across phyla [2] indicates a potential role of nonsense transcripts in regulation of circadian rhythms. Most of the alternatively spliced isoforms harbor in-frame PTCs that arise from full or partial intron retention events. However, a PTC in the RVE2 transcript is introduced through a PCE event. The conservation of AS events and modulation of the relative abundance of nonsense isoforms by environmental and diurnal conditions suggests possible regulatory roles for these alternatively spliced transcripts in circadian clock function. The temperature-dependent expression of the PTC transcripts among members of CCA1/LHY subfamily indicates that alternative splicing may be involved in regulation of the clock temperature compensation mechanism.

Project description:Study on differential gene expression and splicing between wildtype and clock mutants. This study is part of a comparative analysis of the role of Protein Methyltransferase 5 in the regulation of transcriptional and post-transcriptional processes simultaneously in Arabidopsis and Drosophila. Circadian rhythms allow organisms to time biological processes to the most appropriate phases of the day/night cycle1. Post-transcriptional regulation is emerging as an important component of circadian networks2-6, but the molecular mechanisms linking the circadian clock to the control of RNA processing are largely unknown. Here we show that Protein Arginine Methyl Transferase 5 (PRMT5), which transfers methyl groups to arginine residues present in histones7 and Sm spliceosomal proteins8,9, links the circadian clock to the control of alternative splicing in plants. Mutations in prmt5impair multiple circadian rhythms in Arabidopsis thaliana and this phenotype is caused, at least in part, by a strong alteration in alternative splicing of the core-clock gene PSEUDO RESPONSE REGULATOR 9 (PRR9). Furthermore, genome wide studies show that PRMT5 contributes to regulate many pre-mRNA splicing events most likely modulating 5´splice site (5´ss) recognition. PRMT5 expression shows daily and circadian oscillations, and this contributes to mediate the circadian regulation of expression and alternative splicing of a subset of genes. Circadian rhythms in locomotor activity are also disrupted in dart5, a mutant affected in the Drosophila melanogaster PRMT5 homolog, and this is associated with alterations in splicing of the core-clock gene period (per) and several clock associated genes. Our results reveal a key role for PRMT5 in the regulation of alternative splicing and indicate that the interplay between the circadian clock and the regulation of alternative splicing by PRMT5 constitutes a common mechanism that helps organisms to synchronize physiological processes with daily changes in environmental conditions.

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

Publications

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

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