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

Elife. 2019 Jan 10;8:e41770. doi: 10.7554/eLife.41770.

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.

Keywords: autism; genetics; genomics; human; induced neuronal cells; long non-coding RNA; mouse; regenerative medicine; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Cell Differentiation / genetics*
  • Child
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 5 / genetics
  • DNA Copy Number Variations
  • Female
  • Gene Expression Profiling / methods
  • Humans
  • Male
  • Mutation*
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Neurogenesis / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • Pedigree
  • RNA, Long Noncoding / genetics*
  • Translocation, Genetic / genetics

Substances

  • RNA, Long Noncoding