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

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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.

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Direct conversion of fibroblasts to functional neurons by defined factors

Thomas Vierbuchen, Austin Ostermeier, Zhiping Pang … (2010)

Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2, and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine.

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A map of the cis-regulatory sequences in the mouse genome.

Yin Shen, Feng Yue, David F. McCleary … (2012)

The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.

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Rapid single-step induction of functional neurons from human pluripotent stem cells.

Yingsha Zhang, Changhui Pak, Yan Han … (2013)

Available methods for differentiating human embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) into neurons are often cumbersome, slow, and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ESCs and iPSCs can be converted into functional iN cells with nearly 100% yield and purity in less than 2 weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening. Copyright © 2013 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Cheen Euong Ang:

ORCID: http://orcid.org/0000-0002-9050-6122

Qing Ma:

ORCID: http://orcid.org/0000-0001-6812-0584

Orly L Wapinski

ShengHua Fan

Ryan A Flynn

Qian Yi Lee:

ORCID: http://orcid.org/0000-0001-9200-0910

Bradley Coe

Masahiro Onoguchi

Victor Hipolito Olmos

Brian T Do

Lynn Dukes-Rimsky

Jin Xu:

ORCID: http://orcid.org/0000-0003-0944-9835

Koji Tanabe

LiangJiang Wang

Ulrich Elling

Josef M Penninger:

ORCID: http://orcid.org/0000-0002-8194-3777

Yang Zhao

Evan E Eichler:

ORCID: http://orcid.org/0000-0002-8246-4014

Marius Wernig

Howard Y Chang:

ORCID: http://orcid.org/0000-0002-9459-4393

Anne E West: Role: Reviewing Editor

Marianne E Bronner: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 10 January 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e41770

Affiliations

[1 ]deptDepartment of Pathology, Institute for Stem Cell Biology and Regenerative Medicine Stanford University StanfordUnited States

[2 ]deptDepartment of Bioengineering Stanford University StanfordUnited States

[3 ]deptCenter for Personal Dynamic Regulomes Stanford University StanfordUnited States

[4 ]deptDepartment of Dermatology Stanford University StanfordUnited States

[5 ]deptDepartment of Genetics Stanford University StanfordUnited States

[6 ]deptJC Self Research Institute of Human Genetics Greenwood Genetic Center GreenwoodUnited States

[7 ]deptDepartment of Genome Sciences Howard Hughes Medical Institute, University of Washington SeattleUnited States

[8 ]deptDepartment of Genetics and Biochemistry Clemson University ClemsonUnited States

[9 ]deptInstitute of Molecular Biotechnology of the Austrian Academy of Science (IMBA) Vienna Biocenter ViennaAustria

Duke University School of Medicine United States

California Institute of Technology United States

Duke University School of Medicine United States

Author notes

[§]

CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.

[†]

These authors contributed equally to this work.

[‡]

These authors also contributed equally to this work.

Author information

Cheen Euong Ang http://orcid.org/0000-0002-9050-6122

Qing Ma http://orcid.org/0000-0001-6812-0584

Qian Yi Lee http://orcid.org/0000-0001-9200-0910

Jin Xu http://orcid.org/0000-0003-0944-9835

Josef M Penninger http://orcid.org/0000-0002-8194-3777

Evan E Eichler http://orcid.org/0000-0002-8246-4014

Howard Y Chang http://orcid.org/0000-0002-9459-4393

Article

Publisher ID: 41770

DOI: 10.7554/eLife.41770

PMC ID: 6380841

PubMed ID: 30628890

SO-VID: 24b6eb8b-30ea-429b-bc55-ac9ab5a9d1f8

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 09 September 2018

Date accepted : 07 January 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000052, NIH Office of the Director;

Award ID: RO1-HD39331

Award Recipient : Anand Srivastava

Funded by: Self Regional Healthcare Foundation;

Award Recipient : Anand Srivastava

Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;

Award Recipient : Howard Y Chang Evan E Eichler

Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;

Award ID: Faculty Scholar

Award Recipient : Marius Wernig

Funded by: FundRef http://dx.doi.org/10.13039/100000052, NIH Office of the Director;

Award ID: RC4-NS073015

Award Recipient : Marius Wernig Howard Y Chang

Funded by: FundRef http://dx.doi.org/10.13039/100000900, California Institute for Regenerative Medicine;

Award Recipient : Marius Wernig Howard Y Chang

Funded by: FundRef http://dx.doi.org/10.13039/100000052, NIH Office of the Director;

Award ID: P50-HG007735

Award Recipient : Howard Y Chang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement lnc-Nr2f1, a long non-coding RNA focally deleted in autism patients, directly occupies and regulates neuronal genes.

ScienceOpen disciplines: Life sciences

Keywords: long non-coding rna,induced neuronal cells,autism,genomics,human,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: long non-coding rna, induced neuronal cells, autism, genomics, human, mouse

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

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Abstract

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Most cited references 35

Direct conversion of fibroblasts to functional neurons by defined factors

A map of the cis-regulatory sequences in the mouse genome.

Rapid single-step induction of functional neurons from human pluripotent stem cells.

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Cited by 29

Most referenced authors 1,475