Genome complexity: new epigenetic marks (Introduction)

by David Turell , Tuesday, February 28, 2017, 18:07 (2604 days ago) @ David Turell

Not just methylation but now M1A and M6A and others are found but exact function not clear:

http://www.nature.com/nature/journal/v542/n7642/full/542503a.html

"at least one-quarter of our mRNAs harbour chemical tags — decorations to the A, C, G and U nucleotides — that are invisible to today's sequencing technologies. (Similar chemical tags, called epigenetic markers, are also found on DNA.) Researchers aren't sure what these chemical changes in RNA do, but they're trying to find out.

"A wave of studies over the past five years — many of which focus on a specific RNA mark called N6-methyladenosine (m6A) — have mapped these alterations across transcriptomes and demonstrated their importance to health and disease. But the problem is vast: these marks coat not only mRNA but other RNA transcripts as well, and they cut across all the domains of life and beyond, marking even viruses with their presence.

"The modifications themselves are not new. What has given them meaning and driven epitranscriptomics into the spotlight is the discovery of enzymes that can add, remove and interpret them. In 2010, chemical biologist Chuan He at the University of Chicago, Illinois, proposed that these chemical tags could be reversible and important regulators of gene expression. Not long afterwards, his group demonstrated2 the first eraser of these marks on mRNA, an enzyme called FTO. That discovery meant that m6A wasn't just a passive mark — cells actively controlled it. And this realization came at about the same time that global approaches, harnessing the power of next-generation sequencing, made it possible to map m6A and other modifications across the transcriptome.

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"Other RNA modifications have also attracted researchers' attention. In 2016, teams led by chemist Chengqi Yi at Peking University in Beijing and by Rechavi and He used antibody-based methods to map N1-methyladenosine (m1A) in mouse and human cell lines and tissues8. Using different approaches to prevent m1A from interfering with reverse transcription, the two teams showed that m1A, which was discovered in total RNA in the early 1960s, is present on mRNA at the position at which the translation machinery initiates protein production. Stress conditions alter the maps, suggesting that they are dynamic.

"The researchers don't yet know what m1A does, but they have a tantalizing clue: most transcripts have only one m1A site, and these seem to be translated more often than those that lack the modification. “This is very exciting — and of course challenging — because we are dealing with a new regulatory mechanism for translation of messenger RNA,” Rechavi says. An antibody that targets m1A is available from MBL International.

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"Technical hurdles remain, however, as RNA poses challenges not seen in DNA. One is that RNA readily folds in on itself to form loops and knots, so it is highly structured. In its study15, Oxford Nanopore attached RNA to cDNA, which helps 'iron out' the secondary structures and move the RNA through the pore. A second challenge is that RNA degrades more easily than DNA, a problem that may stymie long-read sequencing approaches.

"Yet another challenge, on the data side, is the sheer number of RNA modifications. Recognition of multiple different modifications on the same RNA would require massive training sets to teach the detection software to distinguish one modification from another. Winston Timp, a biomedical engineer at Johns Hopkins University in Baltimore, Maryland, has been using Oxford Nanopore technology to develop new methods for detecting specific DNA modifications. He now plans to move into RNA modifications, developing a training set that will help recognize m6A modifications. “The problem is, we don't know how diverse on a given molecule the modifications are,” he says. “But this is something we can probe. It's an exciting area of research.'”

Comment: We are seeing only the tip of the research iceberg. How much complexity is needed before it is recognized a designer, God, did this.