Chemical tags on RNA, as well as DNA, rediscovered and implying mechanisms involving epigenetics

Chuan He (chemist at Uni­versity of Chicago in Illinois) had been studying a family of proteins that repair damaged DNA, and he began to suspect that these enzymes might also act on RNA. A colleague nearby in the same building, Tao Pan, had been investi­gating specific chemical marks, called methyl groups, that are present on RNAs. At the time, biologists had been getting excited about the epigenome –– that broad array of chemical marks that decorate DNA and its protein scaffold; these marks are known to act like a chem­ical code, telling the cell which genes to express and which to keep silent. As such, the epigenome helps to explain how cells with identical DNA can develop into the multitude of specialized types that make up different tis­sues. The marks help cells in the heart, for example, maintain their identity and not turn into neurons or fat cells. Misplaced epigenetic marks are often found in cancerous cells.

When He and Pan began collaborating [see attached article], most epigenetic research focused on the tags associated with DNA, and the histone proteins that it wraps around. However, more than 100 dif­ferent types of chemical marks had been iden­tified on RNA –– and nobody knew what they did. Some of the enzymes He was studying could strip off methyl groups, and He and Pan wondered whether one of them might work on RNA. Nine years later, “such research has given birth to an ’ome of its own: the epitranscriptome.”

The two researchers and others have shown that a methyl group attached to adenine, one of the four bases in RNA, has crucial roles in cell differentiation, and may contribute to cancer, obesity and more. The governing rule of molecular biology — the central dogma — holds that information flows from DNA to messenger RNA (mRNA) to protein. Many scientists therefore viewed mRNA as little more than a courier, carrying the genetic information encoded in a cell’s nucleus to the protein factories in the cytoplasm. However, in 1974 Fritz Rottman (organic chemist at Michigan State University) first noted methyl groups sometimes on adenine. The modified base is called N6-methyladenosine, m6A.

Rottman et al. speculated that RNA methylation could be a way to select certain transcripts for translation into protein, but it took three decades later –– when mass spectrometry and high-throughput sequencing techniques have become available –– for the proper dissection of this problem. One relevant gene is FTO that encodes aketoglutarate-dependent dioxygenase (FTO), part of the family of methyl-stripping enzymes. It turns out that FTO has the ability to remove the methyl group from m6A.

Interestingly, as an aside, from the earliest genome-wide association studies (GWAS) looking at obesity as the phenotype under study, FTO was consistently found by every GWAS to be almost always the most highly associated gene with obesity. Go figure.

Nature 23 Feb 2o17; 542: 406–408

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