Epigenetic 'switch' regulates RNA-protein interactions

Chemical changes - also known as epigenetic modifications - to messenger RNA (mRNA) are thought to play an important role in gene expression, and have recently been found to affect biological processes such as circadian clock management and obesity. But the specific mechanisms involved have been poorly understood.

A new study by scientists from the University of Chicago now shows that epigenetic modifications to mRNA act as a structural "switch" that - by physically opening space in a folded-up strand of mRNA -allows RNA-binding proteins to recognize and read mRNA regions that would otherwise be inaccessible. The findings, reported in Nature on Feb. 25, provide a new understanding of this emerging field of study.

"RNA affect practically all RNA-protein interactions," said senior study author Tao Pan, PhD, professor of biochemistry and molecular biology at the University of Chicago. "This 'switch' mechanism is expected to work as a master regulator of wide-ranging biological activities through influencing RNA-protein interactions."

The expression of genes is regulated by several different mechanisms. One such mechanism, to DNA, has been well studied for how it contributes to the activation or deactivation of genes. Epigenetic changes to RNA have also been identified, but only recently has this phenomenon - broadly known as the epitranscriptome - been scrutinized for its role in gene expression.

The most abundant epigenetic change to RNA is the addition of a methyl group to certain adenosine nucleotides, known as N6-methyl-adenosine (m6A) modification. This is thought to represent a "code" that affects how RNA-binding proteins read and interpret the genetic instructions conveyed by RNA.

Pan and his colleagues identified specific m6A modifications on an mRNA that increased its interaction with a common RNA-binding protein known as HNRNPC. This protein recognizes and binds to only a specific sequence of nucleotides - five uridines in a row. However, m6A modification only alters adenosine nucleotides. Direct binding to the m6A site by HNRNPC could not explain differences in mRNA-protein interaction.

Unlike the double helix structure of DNA, single-stranded mRNA folds itself into varying and complex structures. The researchers first found that a specific m6A modification they identified was at a location where the RNA strand folded up on itself into a hairpin loop. Here, directly opposite to the m6A site, was a sequence of five uridines in a row - the target binding site for HNRNPC.

The team discovered that the presence of m6A made the target binding site more accessible by physically opening a space for the protein to recognize the site. This increased the affinity of HNRNPC for that RNA. Without m6A, the binding site was hidden within the hairpin and inaccessible.

"RNA-binding proteins such as HNRNPC can have hundreds of thousands of potential binding sites in a cell," Pan said. "Methylation in the RNA structure allows sites that would otherwise be buried to better compete for binding proteins. We call this the m6A switch."

The team verified their findings through a model and an analytical method that allowed them to determine that these uridine sites were reliant on m6A to bind to HNRNPC. They also applied a method to search for these sites throughout the cell, and found almost 40,000 such m6A sites that affected HNRNPC binding, indicating that this phenomenon was widespread and likely could be applied for other protein interactions.

The researchers found that when m6A was removed from these sites, the abundance of the mRNA was lowered, and that there were changes to alternative splicing patterns. "The implication is, of course, that epigenetic changes to the mRNA ultimately change the protein that's created from it, which could be connected to health or disease," Pan said.

The team is now further analyzing the structural and functional consequences of the m6A switch, as well as mutations that affect its function. "We're still learning much about how genes are regulated," Pan adds. "This mechanism represents another layer of epigenetic regulation to , analogous to DNA methylation and histone modification."


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Discovery spotlights key role of mystery RNA modification in cells

More information: Nature DOI: 10.1038/nature14234
Journal information: Nature

Citation: Epigenetic 'switch' regulates RNA-protein interactions (2015, February 25) retrieved 21 August 2019 from https://phys.org/news/2015-02-epigenetic-rna-protein-interactions.html
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JVK
Feb 25, 2015
TB is one of the co-authors of our 1996 Hormones and Behavior review article. She just notified me of this publication, which also links RNA-directed DNA methylation from nutrient-dependent RNA-mediated amino acid substitutions to the pheromone-controlled physiology of reproduction in animals via the light-induced physiology of reproduction in plants.

Article summary: "Epigenetic modifications to mRNA act as a structural 'switch' that allows RNA-binding proteins to recognize and read mRNA regions that would otherwise be inaccessible, a new study has found. The findings provide a new understanding of this emerging field of study."

See our section on molecular epigenetics, for comparison: From Fertilization to Adult Sexual Behavior http://www.hawaii...ion.html

Also see my unpublished invited review: "Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems" posted to figshare.com

Feb 26, 2015
Kohl's co-author merely listed epigenetic changes among all the other then known devices which might possibly be utilized for pheromones to affect nuclear change. They also claimed to have invented what they'd obviously copied from my paper 12 years previously.

JVK
Feb 26, 2015
Bubba Nicholson (aka "TogetherinParis):
Kisses pass epigenetic pheromones in the pathogenesis of sociopathy, 'mental illness', and disease. The cure for crime. The cure for drug addiction. The cure for sexual perversions.
http://www.amazon...04J8HU16 (2011)

Excerpts from our 1996 review: (see the section on Molecular Epigenetics)

"Early in embryonic development attached methyl groups become removed from most genes. Several days later, methyl groups are reattached in appropriate sites. Fascinatingly, some such genes reestablish methylation patterns based upon whether the chromosomal segment carrying the gene came from maternal or paternal chromosomes."

"Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species..."

See also my 2013 review: http://www.ncbi.n...24693353

JVK
Feb 26, 2015
Re: pre-mRNAs and the biophysically constrained molecular mechanisms of cell type differentiation via the RNA-mediated chemistry of protein folding in all cells of all individuals of all species

"The miRNA environment is dynamically regulated, responding to stressors and stimulants within a cell, as well as external factors. As such, miRNA binding site SNPs are not fixed mutations, they are dependent on the miRNAs expressed."
http://www.ncbi.n...4028830/

Many people have not learned the difference between fixed amino acid substitutions that stabilize DNA in the organized genomes of species from microbes to man and mutations that cause physiopathology.

That's why serious scientists are "Combating Evolution to Fight Disease" http://www.scienc...88.short

See also my "RNA-mediated" FB group https://www.faceb...5911912/

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