Featured Research

from universities, journals, and other organizations

No longer junk: Role of long noncoding RNAs in autism risk

Date:
March 24, 2014
Source:
Simons Foundation
Summary:
RNA acts as the intermediary between genes and proteins, but the function of pieces of RNA that do not code for protein has, historically, been less clear. Researchers have ignored these noncoding RNAs until recently for not complying with the central dogma of biology -- that a straight line runs from gene to RNA (transcription) to protein (translation). However, noncoding RNAs are emerging as important regulators of diverse cellular processes with implications for numerous human disorders.

In the past decade, long noncoding RNAs (lncRNAs), which extend longer than 200 nucleotides, have emerged as additional important players in the control of gene expression. They fine-tune the expression of numerous genes and direct the activity of complex regulatory pathways, often in a cell- and developmental-stage-specific manner.
Credit: Julia Yellow

RNA acts as the intermediary between genes and proteins, but the function of pieces of RNA that do not code for protein has, historically, been less clear. Researchers have ignored these noncoding RNAs until recently for not complying with the central dogma of biology -- that a straight line runs from gene to RNA (transcription) to protein (translation). However, noncoding RNAs are emerging as important regulators of diverse cellular processes with implications for numerous human disorders.

Extensive research has already examined the function of microRNAs, a category of small evolutionarily conserved noncoding RNAs about 22 to 24 nucleotides in length that target protein-coding genes in a sequence-specific manner. A plethora of microRNAs are important for brain function and neuropsychiatric diseases, including autism1.

In the past decade, long noncoding RNAs (lncRNAs), which extend longer than 200 nucleotides, have emerged as additional important players in the control of gene expression. They fine-tune the expression of numerous genes and direct the activity of complex regulatory pathways, often in a cell- and developmental-stage-specific manner.

They are found in many places in the genome: within genes, near gene regulatory regions or by themselves (intergenic noncoding RNAs). lncRNAs may overlap with the genetic code for a protein or be expressed in the opposite, or antisense, direction.

In addition to the diversity in their biogenesis, lncRNAs exhibit an impressive versatility of molecular functions. These range from passive influence on the transcription of nearby genes to limiting expression to a paternal or maternal chromosome, a process called imprinting, and inactivating one copy of the X chromosome.

They also interact with chromatin-modifying complexes, which regulate gene expression by changing the packaging of DNA, and with transcription factors that directly regulate gene expression. They may influence RNA splicing, stability and localization and play a role in the translation of RNA to protein and in protein activation. Finally, they may 'sponge' up certain microRNAs, thus blocking their function.

Molecular multitaskers:

The ability of lncRNAs to engage in such molecular multitasking may allow them to link multiple risk factors for genetic disorders into functional networks. This makes them attractive candidates for autism spectrum disorders, which are characterized either by interactions of multiple genes or by disruptions in a single gene that influences numerous molecular pathways.

Whether whole-genome DNA sequencing data will reveal strong genetic links with lncRNAs, as it has for microRNAs, is not yet clear. One thing, though, remains certain: We can no longer overlook such a substantial and active chunk of the transcriptome and characterize it as 'junk' or 'transcriptional noise' if we hope to fully understand complex disorders such as autism.

In the past few years, studies have found alterations in lncRNAs in brains from people with autism, suggesting that they contribute to autism risk. For example, MSNP1AS, a lncRNA transcribed from a region of chromosome 5 that carries an autism-associated variant, is elevated in the cortex of people with autism who also carry the disease-related variant. MSNP1AS may regulate moesin, a gene important for the structure of neurons' signal-receiving branches, or dendrites, and immune system activation.

Last year, a carefully conducted study identified numerous lncRNAs that are robustly dysregulated in autism postmortem brain samples. Impressively, some disease-altered lncRNAs are found near important autism-linked genes such as BDNF and SHANK2.

Another lncRNA with potential implications for autism is LOC389023, which regulates DPP10, a gene linked to autism and other neurodevelopmental disorders. DPP10 controls the structure and function of neuronal junctions, or synapses, via its effects on potassium ion channels3.

Last year, researchers used a similar approach to study the expression of lncRNAs in a mouse model of Rett syndrome. One lncRNA (AK081227) that is expressed at abnormal levels in these mice controls the expression of its host protein-coding gene, the gamma-aminobutyric acid receptor subunit Rho 2 (GABRR2), which has also been linked to autism.

Additional reports have linked other lncRNAs to autism, such those that travel antisense to the FMR1 and UBE3A genes. Mutations in these genes underlie fragile X syndrome and Angelman syndrome, respectively. Other studies have also uncovered a subset of lncRNAs expressed from the autism-linked PTCHD1 gene and the 7q31 chromosomal region.

In addition, the lncRNA ZNF127AS has altered expression in the brains of people with Prader-Willi syndrome. On a similar note, a cluster of small nucleolar RNAs -- which despite their name are a category of lncRNAs -- are encoded by the paternally inherited microdeletion at 15q11.2 that is also linked to Prader-Willi syndrome.

Brain builders:

Previous work has identified a subset of lncRNAs that are important for regulating the birth of new neurons, or neurogenesis, and the process by which synapses adapt to experience, called synaptic plasticity.

Of particular importance is the finding that the intergenic noncoding RNA MALAT1, one of the most highly expressed lncRNAs in the brain, can regulate the formation of new synapses, or synaptogenesis. It does this by associating inside the nucleus with multiple RNA splicing factors and influencing the expression of autism-linked genes, such as NLGN1.

Intriguingly, there are several other links between MALAT1 and autism-associated factors. For example, beta-catenin -- an important component of the WNT signaling pathway that has been linked to multiple neuropsychiatric disorders -- activates MALAT1 transcription. CREB, another transcription factor known for its role in activity-dependent gene expression, also binds to MALAT1. Notably, CREB may control MALAT1 transcription following exposure to the peptide hormone oxytocin, which has also been linked to autism.

MALAT1 and another lncRNA, BDNFOS, which has the antisense, or opposite, code to that of the autism-linked BDNF gene, are expressed in conjunction with neuronal activity. On the other hand, GOMAFU, a lncRNA whose levels are dampened in postmortem brains from people with schizophrenia, is significantly suppressed following the activation of mouse cortical neurons.

Other lncRNAs run antisense to important synaptic plasticity-related genes, such as NRGN, CAMK2N1 and CAMKK1. lncRNAs are also associated with genes linked to changes in the synapse that occur after exposure to cocaine. Interestingly, a novel subset of lncRNAs are expressed from the regulatory elements of genes, such as c-FOS and ARC, that regulate gene transcription in response to neuronal activity.

Adding to their important role in brain plasticity, lncRNAs are highly expressed during prenatal neurogenesis and are important for maintaining and differentiating the precursors to neurons: neural stem cells and neuronal progenitors. Of particular interest is the lncRNA EVF2, which runs antisense to the regulator gene DLX5,6 and plays a crucial role in the birth of neurons that dampen brain activity. This adds another layer to the role of lncRNAs in cell-type-specific neuronal functions.

Despite these many threads, much more work is needed to determine the exact mechanisms of action and the physiological significance of lncRNAs for autism and other neurodevelopmental disorders.


Story Source:

The above story is based on materials provided by Simons Foundation. Note: Materials may be edited for content and length.


Cite This Page:

Simons Foundation. "No longer junk: Role of long noncoding RNAs in autism risk." ScienceDaily. ScienceDaily, 24 March 2014. <www.sciencedaily.com/releases/2014/03/140324133117.htm>.
Simons Foundation. (2014, March 24). No longer junk: Role of long noncoding RNAs in autism risk. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/2014/03/140324133117.htm
Simons Foundation. "No longer junk: Role of long noncoding RNAs in autism risk." ScienceDaily. www.sciencedaily.com/releases/2014/03/140324133117.htm (accessed August 20, 2014).

Share This




More Health & Medicine News

Wednesday, August 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola-Hit Sierra Leone's Freetown a City on Edge

Ebola-Hit Sierra Leone's Freetown a City on Edge

AFP (Aug. 19, 2014) Residents of Sierra Leone's capital voice their fears as the Ebola virus sweeps through west Africa. Duration: 00:56 Video provided by AFP
Powered by NewsLook.com
101-Year-Old Working Man Has All The Advice You Need

101-Year-Old Working Man Has All The Advice You Need

Newsy (Aug. 19, 2014) Herman Goldman has worked at the same lighting store for almost 75 years. Find out his secrets to a happy, productive life. Video provided by Newsy
Powered by NewsLook.com
Researcher Testing on-Field Concussion Scanners

Researcher Testing on-Field Concussion Scanners

AP (Aug. 19, 2014) Four Texas high school football programs are trying out an experimental system designed to diagnose concussions on the field. The technology is in response to growing concern over head trauma in America's most watched sport. (Aug. 19) Video provided by AP
Powered by NewsLook.com
American Ebola Patient Apparently Improving, Outbreak Is Not

American Ebola Patient Apparently Improving, Outbreak Is Not

Newsy (Aug. 19, 2014) Nancy Writebol, an American missionary who contracted Ebola, is apparently getting better, according to her husband. The outbreak, however, is not. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins