1. Genetics and Genomics
  2. Stem Cells and Regenerative Medicine
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The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders

  1. Cheen Euong Ang
  2. Qing Ma
  3. Orly L Wapinski
  4. ShengHua Fan
  5. Ryan A Flynn
  6. Qian Yi Lee
  7. Bradley Coe
  8. Masahiro Onoguchi
  9. Victor Hipolito Olmos
  10. Brian T Do
  11. Lynn Dukes-Rimsky
  12. Jin Xu
  13. Koji Tanabe
  14. LiangJiang Wang
  15. Ulrich Elling
  16. Josef M Penninger
  17. Yang Zhao
  18. Kun Qu
  19. Evan E Eichler
  20. Anand Srivastava
  21. Marius Wernig  Is a corresponding author
  22. Howard Y Chang  Is a corresponding author
  1. Stanford University, United States
  2. Greenwood Genetic Center, United States
  3. Howard Hughes Medical Institute, University of Washington, United States
  4. Clemson University, United States
  5. Institute of Molecular Biotechnology of the Austrian Academy of Science, Austria
Research Article
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Cite this article as: eLife 2019;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.

Article and author information

Author details

  1. Cheen Euong Ang

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Qing Ma

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Orly L Wapinski

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. ShengHua Fan

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ryan A Flynn

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Qian Yi Lee

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9200-0910
  7. Bradley Coe

    Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Masahiro Onoguchi

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Victor Hipolito Olmos

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian T Do

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lynn Dukes-Rimsky

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jin Xu

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0944-9835
  13. Koji Tanabe

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. LiangJiang Wang

    Department of Genetics and Biochemistry, Clemson University, Clemson, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Ulrich Elling

    Vienna Biocenter, Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  16. Josef M Penninger

    Vienna Biocenter, Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8194-3777
  17. Yang Zhao

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Kun Qu

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Evan E Eichler

    Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8246-4014
  20. Anand Srivastava

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Marius Wernig

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    For correspondence
    wernig@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
  22. Howard Y Chang

    Center for Personal Dynamic Regulomes, Stanford University, Stanford, United States
    For correspondence
    howchang@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9459-4393

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.

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).

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: September 9, 2018
  2. Accepted: January 7, 2019
  3. Accepted Manuscript published: January 10, 2019 (version 1)

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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