1. Genetics and Genomics
Download icon

Neurodevelopmental Disorders: Beyond protein-coding genes

  1. Anna Lozano-Ureña
  2. Sacri R Ferrón  Is a corresponding author
  1. University of Valencia, Spain
Insight
  • Cited 1
  • Views 1,243
  • Annotations
Cite this article as: eLife 2019;8:e45123 doi: 10.7554/eLife.45123

Abstract

A long non-coding RNA called lnc-NR2F1 regulates several neuronal genes, including some involved in autism and intellectual disabilities.

Main text

Most of the mammalian genome does not encode for working proteins. However, much of this non-coding DNA is still transcribed, often to produce RNA products that have a role in development. Some of these molecules are called long non-coding RNAs (lncRNAs) because they contain more than 200 base pairs: these transcripts fine-tune gene expression by interacting with chromatin and the transcription machinery inside cells (Ponting et al., 2009). The brain expresses more lncRNAs than any other part of the body (Derrien et al., 2012), but we know relatively little about the roles these molecules play in this organ (D'haene et al., 2016; Aprea et al., 2013). Learning more about lncRNAs will be essential if we are to understand both the typical and the atypical brain.

In intellectual disabilities or autism spectrum disorders, defects in cognitive abilities, such as social interaction and communication, can appear early in development and persist into adulthood. These neurodevelopmental disorders involve abnormal changes in the way genetic information is expressed (Rennert and Ziats, 2017). Several lncRNAs are associated with these conditions, sometimes being transcribed atypically (reviewed in van de Vondervoort et al., 2013). For instance, certain lncRNAs are expressed differently in patients on the autism spectrum (Ziats and Rennert, 2013).

Now, in eLife, Anand Srivastava, Marius Wernig, Howard Chang and colleagues – including Cheen Ang, Qing Ma and Orly Wapinski, all from Stanford University, as joint first authors – report that several lncRNAs that are involved in the formation of neurons are mutated or disrupted in children with autism spectrum disorder and intellectual disabilities (Ang et al., 2019).

Ang et al. started by reprogramming mouse cells called embryonic fibroblasts into neurons; this experiment helped them to identify 35 candidate lncRNAs that are both upregulated when neurons form and close to neuronal genes. Amongst those, 28 were present on the same chromosomes in humans and in mice. The group then tried to identify whether these 28 human candidates were mutated in disease by overlapping the lncRNAs sequences onto a map of mutations found in children with neurodevelopmental disorders and congenital defects. This analysis highlighted five lncRNAs that were often mutated in affected individuals, and which happened to also be expressed during human brain development. One of them, called lnc-NR2F1, was adjacent to NR2F, a gene which encodes a transcription factor that helps neurons form and wire together (Borello et al., 2014).

The team, which is based at Stanford, Clemson University, the University of Washington, the Greenwood Genetic Center, and the Austrian Academy of Sciences, found patients with developmental delays who expressed normal levels of the coding NR2F1 gene but presented a unique disruption of the lnc-NR2F1 gene. Most of the brain lncRNAs are located near genes that code for proteins, and it is believed that both lncRNAs and protein-coding genes are expressed at the same time (Ponjavic et al., 2009). However, the work by Ang et al. potentially indicates that lnc-NR2F1, rather than NR2F1, might contribute to the clinical symptoms associated with neurodevelopmental disorders. If so, this would strengthen the hypothesis that lncRNAs are independent transcriptional units that activate gene expression in the brain.

Then, Ang et al. discovered that, in mouse cells, lnc-Nr2f1 enhanced the transcription of genes that create and guide the structures which allow neurons to connect. Deleting or overexpressing lnc-Nr2f1 changed how these genes were expressed, and how the cells looked and worked. In addition, lnc-Nr2f1 was shown to attach to the genes, suggesting that it binds chromatin to regulate gene expression (Figure 1). While we still do not fully understand the physiological changes that accompany neurodevelopmental disorders, the results by Ang et al. suggest that lncRNAs themselves may contribute to these conditions, or that they drive the expression of disease-associated genes.

Long non-coding RNAs (lncRNAs) and neuronal development in neurodevelopmental disorders.

Mouse embryonic fibroblasts (orange) were reprogrammed into neurons (top right) using transcription factors called BAM factors. This led to an increase in the expression of neuronal genes (green triangle) and lncRNAs (pink triangle). Of the 287 lncRNAs that were differentially expressed, 35 were close to neuronal genes. One of these, lnc-Nr2f1 (red loops), binds to mouse neuronal and axon guidance genes (black boxes) and promotes their transcription (green arrow). The overexpression of lnc-Nr2f1 resulted in 311 neuronal genes being upregulated and 32 being repressed. The expression of lnc-NR2F1 is altered (red cross) in patients with autism spectrum disorders and intellectual disabilities, and this potentially disrupts the transcription of human neuronal and axon guidance genes (brown boxes; black inhibitory arrow). It is therefore possible that lnc-NR2F1 is involved in these conditions.

How mutations in protein-coding genes contribute to disease is widely studied, yet most mutations are found in regions that do not code for proteins. Understanding how lncRNAs regulate genes during brain development provides a way to tie genetic variation with changes in gene expression in neurodevelopmental disorders. Building on the findings by Ang et al., it may be possible to examine how clinical phenotypes, cellular responses and lncRNAs are connected in these conditions, potential unearthing new targets for therapeutic intervention.

References

Article and author information

Author details

  1. Anna Lozano-Ureña

    Anna Lozano-Ureña is in the Department of Cell Biology, University of Valencia, Valencia, Spain

    Competing interests
    No competing interests declared
  2. Sacri R Ferrón

    Sacri R Ferrón is in the Department of Cell Biology and ERI BiotecMed, University of Valencia, Valencia, Spain

    For correspondence
    sacramento.rodriguez@uv.es
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0854-8575

Publication history

  1. Version of Record published: February 19, 2019 (version 1)

Copyright

© 2019, Lozano-Ureña and Ferrón

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.

Metrics

  • 1,243
    Page views
  • 132
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Bernard Y Kim et al.
    Tools and Resources Updated

    Over 100 years of studies in Drosophila melanogaster and related species in the genus Drosophila have facilitated key discoveries in genetics, genomics, and evolution. While high-quality genome assemblies exist for several species in this group, they only encompass a small fraction of the genus. Recent advances in long-read sequencing allow high-quality genome assemblies for tens or even hundreds of species to be efficiently generated. Here, we utilize Oxford Nanopore sequencing to build an open community resource of genome assemblies for 101 lines of 93 drosophilid species encompassing 14 species groups and 35 sub-groups. The genomes are highly contiguous and complete, with an average contig N50 of 10.5 Mb and greater than 97% BUSCO completeness in 97/101 assemblies. We show that Nanopore-based assemblies are highly accurate in coding regions, particularly with respect to coding insertions and deletions. These assemblies, along with a detailed laboratory protocol and assembly pipelines, are released as a public resource and will serve as a starting point for addressing broad questions of genetics, ecology, and evolution at the scale of hundreds of species.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Benjamin M Moran et al.
    Review Article

    In the past decade, advances in genome sequencing have allowed researchers to uncover the history of hybridization in diverse groups of species, including our own. Although the field has made impressive progress in documenting the extent of natural hybridization, both historical and recent, there are still many unanswered questions about its genetic and evolutionary consequences. Recent work has suggested that the outcomes of hybridization in the genome may be in part predictable, but many open questions about the nature of selection on hybrids and the biological variables that shape such selection have hampered progress in this area. We synthesize what is known about the mechanisms that drive changes in ancestry in the genome after hybridization, highlight major unresolved questions, and discuss their implications for the predictability of genome evolution after hybridization.