Zohreh Talebizadeh1, Ayten Shah1, Luciano DiTacchio2. 1. Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri. 2. University of Kansas Medical Center, Kansas City, Kansas.
Abstract
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.
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.