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Research by Professor Yang Shi and colleagues suggests that METTL3-mediated RNA methylation promotes productive transcription.

RNA can be chemically modified by the addition of methyl groups by the enzyme METTL3 to form m6A RNA. m6A is known to regulate several aspects of RNA biology such as RNA stability. However, although previous studies have shown that this modification is added at the same time as the RNA is being transcribed from DNA, it is not yet known whether m6A has a role in regulating transcription itself.

To address this question, Professor Yang Shi and colleagues from Fudan University and Harvard Medical School studied the localisation of the METTL3-containing complex in the genome. In their paper published in Molecular Cell, they show that METTL3 widely co-localises with regions that regulate transcription (promoters and enhancers) and deposits m6A on RNAs at these sites.

By using a technique that specifically analyses RNAs that are still in the process of being produced (so-called nascent RNAs), the team observed that nascent RNA production was decreased at promoters and enhancers when the METTL3 enzyme is depleted. This suggests a role of m6A in promoting transcription of nascent RNA.

To uncover a possible mechanism for this observation, the researchers noticed that genes that have less METTL3 associated with them are those that are targeted by a complex called Integrator, which acts to prematurely terminate the production of nascent RNA. Upon experimental depletion of METTL3 or proteins that bind to m6A, levels of Integrator increased at promoters and enhancers.

Put together, the evidence suggests that METTL3-mediated nascent RNA m6A methylation is able to protect nascent RNA during its production from Integrator-induced premature termination to promote productive transcription. This newly uncovered role of m6A adds to the other observed impacts of this modification on RNA biology and highlights the complex functionality of m6A in RNA regulation.

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