A growing body of evidence supports the potential role of the circadian system and chromatin remodeling genes in autism. Considering the heterogeneity and gender discrepancy in autism, and the complex nature of the epigenetic landscape, identification of biologically relevant epigenetic factors requires reducing heterogeneity using proper subtyping. For this study, we used X chromosome inactivation (XCI) status in females with autism as an epigenetic marker for subtyping and examined the expression level of members of KDM5, a chromatin remodeling gene family. KDM5 are histone demethylases involved in the circadian molecular machinery. We used human blood samples to characterize alternatively spliced KDM5 isoforms and noticed that KDM5C undergoes a complex splicing process. We also identified a KDM5C isoform (KDM5C-3'UTR-lncRNA) containing a novel 3'UTR originated from a retrotransposed gene (retro-SUV39H2) of an autosomal methyltransferase (SUV39H2). This 3'UTR shows 84% sequence homology with long ncRNAs (lncRNAs) and is located 32 kb downstream of KDM5C. The KDM5C-3'UTR-lncRNA isoform was differentially expressed in autistic females with XCI skewness compared with controls. KDM5C plays a crucial role in balancing histone H3K4 methylation states. The identified retro-SUV39H2 originated lncRNA also shows H3K4 marks. By assessing the expression level of alternatively spliced Kdm5 isoforms at different circadian time-points, we showed that some isoforms follow a circadian oscillation pattern in wild type mouse brain.This study provides the first evidence and a suggestive model for the potential role of retrotransposed elements in autism through linking methylases and demethylases, two functionally complementary components of chromatin remodeling, which may collectively contribute to disease etiology through lncRNAs. Autism Res 2019, 12: 1007-1021. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Genes do not function in isolated conditions and their proper expression level also depends on a mechanism called gene regulation. An example of gene regulation is when changes outside DNA sequences influence the function of autism susceptibility genes. Alternative splicing is one type of gene regulation, which produces several versions of a gene (called variants) that may slightly differ from each other and be expressed at different levels in response to environmental changes. The circadian clock is an essential timing mechanism that enables organisms to maintain internal processes in sync with the dynamic environment brought about by the day-night cycle. The goal of this study was to assess if a subset of females with autism with certain genetic marker had a unique pattern of alternative splicing of three circadian genes. We identified a novel variant that is differentially expressed in this subset. Our study provides a novel subject stratification strategy, and a suggestive model of how biologically relevant components of a gene regulatory process may be linked and, possibly, collectively contribute to the etiology of autism.
Keywords: alternative splicing; autism; chromatin genes; circadian; long noncoding RNAs; retrotransposons.
© 2019 International Society for Autism Research, Wiley Periodicals, Inc.