Abstract
Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.
Highlights
Eukaryotic genomes are extensively transcribed to produce long non-coding RNAs in a temporally and spatially regulated manner (Flynn and Chang, 2014)
58% of the changed transcripts corresponded to non-coding genes while only 42% of them corresponded to coding genes
Consistent with target genes in our lnc-Nr2f1 overexpression study, we found lnc-Nr2f1 KO led to down regulation of neuronal pathfinding and axon guidance genes such as Sema6d and proneural basic helix loop helix (bHLH) transcription factor Neurod2 as well as deregulation of genes associated with autism spectrum disorder such as Bdnf, Dcx and Nlgn3 (Basu et al, 2009) (Figure 3G)
Summary
Eukaryotic genomes are extensively transcribed to produce long non-coding RNAs (lncRNAs) in a temporally and spatially regulated manner (Flynn and Chang, 2014). Efforts to identify genetic variation linked to human disease through genome-wide association studies revealed a significant majority affecting the non-coding landscape. Based on their expression and diversity in the mammalian brain, we postulate neuronal lncRNAs may be recurrently affected by mutations that disrupt normal brain function. Despite recent findings that have greatly increased the number of protein coding genes implicated in human intellectual disability and autism, a majority of patients lack well-understood genetic lesions which include a large number of inherited variants occur in noncoding regions that could not be interpreted (Iossifov et al, 2014; Ronemus et al, 2014; Gilman et al, 2011; Iossifov et al, 2012; De Rubeis et al, 2014; O’Roak et al, 2012a; O’Roak et al, 2012b; Hormozdiari et al, 2015). We show that one of these lncRNAs, lnc-NR2F1 participates in neuronal maturation programs in vitro by regulating the expression of a network of genes previously linked to human autism
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