The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders
- Stanford University, United States
- Greenwood Genetic Center, United States
- Howard Hughes Medical Institute, University of Washington, United States
- Clemson University, United States
- Institute of Molecular Biotechnology of the Austrian Academy of Science, Austria
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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE115079.
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A Transcriptomic Atlas of Mouse Neocortical LayersNCBI Gene Expression Omnibus, GSE27243.
Article and author information
Author details
Funding
NIH Office of the Director (RC4-NS073015)
- Marius Wernig
- Howard Y Chang
NIH Office of the Director (P50-HG007735)
- Howard Y Chang
California Institute for Regenerative Medicine
- Marius Wernig
- Howard Y Chang
NIH Office of the Director (RO1-HD39331)
- Anand Srivastava
Self Regional Healthcare Foundation
- Anand Srivastava
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anne E West, Duke University School of Medicine, United States
Ethics
Animal experimentation: All mouse work was performed according to IACUC approved protocols at Stanford University (APLAC-21565). Samples in the paper were obtained without determining their sex. All animals were housed in an animal facility with a 12hr light/dark cycle.
Human subjects: The study protocol, consent form, consent to publish and privacy practices were reviewed and approved by the Institutional Review Board of the Self Regional Healthcare, Greenwood, SC (Reference number Pro00074882).
Version history
- Received: September 9, 2018
- Accepted: January 7, 2019
- Accepted Manuscript published: January 10, 2019 (version 1)
- Version of Record published: February 19, 2019 (version 2)
Copyright
© 2019, Ang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders
eLife 8:e41770.
https://doi.org/10.7554/eLife.41770
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