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Cornell Team Finds Widespread Adenosine Methylation in Mammalian Transcripts

NEW YORK (GenomeWeb News) – An epigenetic modification that involves the methylation of adenosine in RNA is more common in mammalian cells than previously appreciated, according to a study online today in Cell.

A Cornell University team used immunoblotting, along with an antibody-based enrichment and sequencing method dubbed MeRIP-Seq, to look at N6-methyladenosine profiles in messenger RNA and non-coding RNAs from several mammalian tissues and cell lines.

Their analyses suggest that the modification is reversible and found in transcripts from tissues throughout the body, apparently contributing to tissue-specific processes. In addition to the biological insights offered by the study, those involved say the work also sets the stage for future studies on the RNA modification.

"These findings provide a resource for identifying transcripts that are substrates for adenosine methylation and reveal novel insights into the epigenetic regulation of the mammalian transcriptome," co-corresponding authors Christopher Mason and Samie Jaffrey and colleagues wrote.

Past studies have mainly detected N6-methyladenosine in transfer RNA, ribosomal RNA, and viral RNA, the team noted, with the post-transcriptional modification being identified only rarely in mammalian transcripts in vivo.

Nevertheless, they added, a study published by an international team in Nature Chemical Biology last year demonstrated that the obesity-related metabolic gene FTO can act as a demethylase enzyme removing the adenosine methylation mark.

That finding, coupled with studies showing fairly high levels of methylated adenosine in total cellular DNA, hint that the RNA modification might be more common in mammalian transcripts than was realized, Mason, Jaffrey, and co-authors explained, perhaps contributing to dynamic epigenetic changes on RNA that are comparable to cytosine methylation and hydroxymethylation in DNA.

To look at this in more detail, the researchers used MeRIP-Seq with the Illumina GAIIx or HiSeq 2000 to assess N6-methyladenosine patterns in RNA from mouse brain samples, cells from the human embryonic kidney cell line HEK293T, and other animal samples. They also used immunoblotting to look at levels of the mark in transcripts from mouse tissues, rat brain samples, and human cell lines.

Overall, the team found that the adenosine methylation mark was over-represented in transcripts from the brain, especially in samples collected in adulthood and later stages of brain development. It was also enriched in mRNAs from the liver and kidney.

The mark turned up in transcripts from all of the tissues tested, including more than 300 non-coding mammalian RNAs and nearly 7,700 mRNAs. In terms of its location in transcripts, researchers reported that N6-methyladenosine tended to fall in evolutionarily conserved regions, within 3' untranslated regions, microRNA binding sites, and near stop codons.

The team already started exploring interactions between FTO demethylase levels and transcript adenosine methylation patterns. And, they say, additional work will help in unraveling how N6-methyladenosine profiles RNA shift in individuals carrying mutations to the FTO gene, if at all.

"The pervasive nature of this modification suggests that adenosine methylation has important roles in RNA biology," the study's authors concluded, arguing that reversible adenosine methylation in RNA "is likely to influence a wide variety of biological pathways and physiological processes."

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