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Circadian Network and Autism: Unusual Alternative Splicing Pattern of the JARID1 Genes
Objectives: To investigate the role of circadian genes and their potential mis-splicing in autism.
Methods: We evaluated the expression level of multiple JARID1 alternative splicing transcripts in autistic subjects stratified based on the absence or presence of a given DNA methylation-related marker (DM) in lymphoblastoid cell line-derived RNAs, using Exon array profiling, TaqMan assays, followed by DNA sequencing. Expression levels of the identified isoforms were also investigated in the brain samples from control and a Jarid1 mice model at different circadian timing.
Results: A distinct pattern was detected in the expression level of alternatively spliced JARID1 isoforms for autistic subjects with DM compared to those without DM and controls. Additional experiments, including miRNA mimics, are underway to further characterize the role of miR132 in regulating JARID1a by finding which isoforms(s) show miR132-dependent expression.
Conclusions: This is the first study to evaluate a clock gene in autism, at the alternative splicing level in conjunction with DM markers. Our data indicates an unusual splicing process for the X-linked member of this circadian gene family (JARID1c), resulting in unusually high level of intron retained isoforms, as well as the potential role of the long noncoding RNAs and circular RNAs in the regulation of this circadian gene expression.