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New Data Reveal Role of Epigenetic Switch in RNA-Protein Interactions

NEW YORK (GenomeWeb) – A new report out of the University of Chicago has uncovered new details about how epigenetic changes to messenger RNA influence cell viability and development, demonstrating how one type of posttranscriptional modification gives RNA-binding proteins access to previously inaccessible regions of the mRNA.

"RNA epigenetic modifications affect practically all RNA-protein interactions," Tao Pan, senior author of the study, said in a statement. "This 'switch' mechanism is expected to work as a master regulator of wide-ranging biological activities through influencing RNA-protein interactions."

Of the various epigenetic changes that can occur in eukaryotic mRNA, the most common is the addition of a methyl group to certain adenosine nucleotides. Called N6-methyl-adenosine (m6A) modification, this event has been shown to be selectively recognized by the human YTH domain family 2 protein to regulate mRNA degradation. Still, the mechanisms underlying m6A's physiological role remain unclear.

As they wrote in a paper appearing this week in Nature, Pan and his colleagues discovered in human cells that m6A controls the RNA-structure-dependent accessibility of single-stranded RNA binding motifs to control RNA-protein interactions for biological regulation — a process they dubbed the "m6A switch."

Specifically, m6A was found to alter the local structure in mRNA and long non-coding RNA to permit the binding of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an abundant nuclear RNA-binding protein responsible for pre-mRNA processing.

Using photoactivatable-ribonucleotide-enhanced crosslinking and immunoprecipitation, or PAR-CLIP, and anti-m6A immunoprecipitation, the team was able to uncover more than 39,000 m6A switches among HNRNPC binding sites. When m6A levels were reduced, HNRNPC binding was lowered at roughly 2,800 high-confidence m6A switches.

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

The researchers also demonstrated that m6A switch-regulated HNRNPC-binding activities can alter both the abundance and alternative splicing of mRNAs, highlighting the regulatory role of m6A switches on gene expression and RNA maturation.

Currently, Pan and his group are investigating additional structural and functional roles of m6A switches, as well as how mutations can alter their activity.

"We're still learning much about how genes are regulated," he said. "This mechanism represents another layer of epigenetic regulation to gene expression, analogous to DNA methylation and histone modification."