Poster abstracts
Poster number 105 submitted by Krithika R Subramanian
Time-dependent differential alternative splicing in mammalian tissues
Krithika R Subramanian (Department of Pharmacology and System Physiology, University of Cincinnati and Department of Pediatrics, Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Research Center), Nathan Salomonis (Department of Pediatrics, Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Research Center and Department of Biomedical Informatics, University of Cincinnati), Christian I Hong (Department of Pharmacology and System Physiology, University of Cincinnati )
Abstract:
Abstract:
Recent data suggests that alternative splicing (AS) may play a profound role in the temporal regulation of RNA transcripts to maintain circadian rhythm (CR). Mammalian CR is controlled by a core clock molecular complex in the hypothalamus and downstream by clock controlled genes (CCGs). Dysfunctional CR is implicated in sleep, behavioral, neurological disorders and even in cancer. Though AS is proven to add a regulatory layer of control in addition to transcription regulation, its exact role in establishing or maintaining the core clock and other peripheral clocks in organ systems are not well studied. To establish a critical link between AS and CR across multiple mammalian tissues and develop automated bioinformatics workflows for these analyses, we performed a deep analysis of RNA-Seq data from 12 tissues in mice, sampled every 6 hrs for a 48hr time course.
Using non-parametric periodicity detection algorithms we identified thousands of rhythmic splicing events, with varying frequencies among the different tissues examined. Comparison of these splicing events and genes across circadian RNA-Seq datasets by-and-large confirmed the validity of these predictions, with improved accuracy relative to exon microarray circadian splicing predictions. From these data, we observe a disproportionate number of splicing events relative to circadian gene expression changes across the same tissues, particularly in the brain, which has the highest proportion of splicing events (17% of all events detected). While a high percentage of circadian transcriptional regulation occurred in the Heart, Brown adipose, Skeletal Muscle and Liver, these same tissues showed some of the least frequent circadian splicing (~5% of all events in each). We also observe that the large majority of the rhythmic splicing events are tissue specific whereas, a small proportion is (n=49) consistently regulated across multiple tissues (n≥5). These data suggest that alternative splicing differentially tunes circadian expression in specific tissues, likely regulated by tissue specific splicing regulators. Further understanding of the role of these splicing regulators and splicing events may yield prospective chrono-therapeutic targets, which we aim to evaluate experimentally.
Keywords: Alternative splicing, Circadian rhythm