The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders

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.

Functional classification of noncoding RNAs associated with distinct histone modifications by PIRCh-seq

“…In our NPC PIRCh-seq, a lncRNA upstream of the Nr2f1 gene, lnc-Nr2f1 , was retrieved by the promoter marks histone H3K4me3 ( P <0.05), but not enhancer-associated nor repressive modifications (H3K27ac and H3K27me3), indicating that this lncRNA may preferentially associate with H3K4me3 regions ( Figure 1E ). Recently, lnc-Nr2f1 was reported to play a critical role in regulating neurodevelopmental disorders 32 . In order to further validate the chromatin-RNA association of this lncRNA, we retrieved lnc-Nr2f1 RNA and mapped its associated DNA elements in NPCs (ChIRP-seq experiment).…”

“…To determine the genome-wide localization of lnc-Nr2f1 1 we followed protocols previously described 2 . ChIRP was performed using biotinylated probes designed against mouse lnc-Nr2f1 using the ChIRP probes designer (Biosearch Technologies).…”

Long Noncoding RNAs in Development and Regeneration of the Neural Lineage

“…A later study found that RMST interacts with SOX2 and promotes SOX2 binding to its target sites in the genome during neuronal differentiation (Ng et al 2013). In haploid mESCs, the overexpression and genetic perturbation of lnc-Nr2f1 led to dysregulation of hundreds of genes as the cells were differentiated into neurons, with down-regulated genes related to neuronal pathfinding and axon guidance (Ang et al 2019). Conversely, overexpression of lnc-Nr2f1 during ESC differentiation and during reprogramming of mouse embryonic fibroblasts (MEFs) to induced neurons (iNs) led to increased neurite length and increased neural conversion (Ang et al 2019).…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…For example, a chromosomal translocation that specifically disrupts the non-coding RNA lnc-NR2F1 has been associated with neurodevelopmental disorders. 106 Long non-coding RNAs have been also proposed to promote cardiac regeneration and function after myocardial infarction, 107 suggesting their potential application also in cardiovascular disease treatment.…”