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25.04.19 m7G is a new RNA-modification pathway with phenotypic effects

last modified Apr 25, 2019 04:24 PM
The Kouzarides lab identify a METTL1-dependent modification of RNA, N7-methylation of guanosine, as a new modification pathway regulating miRNA structure and biogenesis, with a phenotypic effect on cancer cell migration

METTL1 promotes let-7 microRNA processing via m7G methylation 

Pandolfini L, Barbieri I et al. (2019) Molecular Cell, 25 April

DOI: https://doi.org/10.1016/j.molcel.2019.03.040

 

Media release  

RNA molecules, similarly to proteins, are subject to chemical modifications, which together constitute the 'epitranscriptome'. While over 110 RNA modifications have been identified so far, the precise location and function of only very few of them are known at the molecular level.

In a paper published today in the journal Molecular Cell, the Kouzarides lab identifies for the first time the presence of the modification N7-methylation of guanosine (7-methylguanosine or m7G) in a class of small regulatory RNAs known as microRNAs (miRNAs). They developed a unique chemical mapping method to identify the precise sites of the m7G modification, which can be applied to any kind of RNA, including the very small miRNAs. 

Pandolfini, Barbieri and co-workers at the Gurdon Institute, University of Cambridge, show that the RNA methyltransferase METTL1 is the enzyme required for m7G modification of a specific class of tumour-suppressor miRNAs, including the well-known let-7 family. The presence of the m7G modification prevents formation of secondary structures in miRNA precursors that would otherwise inhibit the normal processing pathway for miRNA biosynthesis.

The researchers created a human lung cancer cell line in which they knocked down the gene for METTL1 and examined the cell behaviour with an in vitro cell migration assay. They found that there was a defective production of specific miRNAs, and a precise functional consequence, namely the loss of inhibition of lung cancer cell migration.

Pandolfini m7G pathway

Proposed model of the role of METTL1-mediated m7G in promoting miRNA processing and suppressing migration phenotype

These data characterise a novel epitranscriptomic pathway, including an enzyme catalysing the modification and its RNA substrates, the structural consequences of the modification and its defined phenotypic effects.

The high-throughput mapping of m7G in miRNAs was facilitated by the authors developing a novel sequencing technique that includes a borohydride reduction step to specifically react with m7G, alongside RNA immunoprecipitation. This methodology is now available to be applied to any other RNA type in future studies.  

The position of the methyl group on Nitrogen 7 of the guanosine ring is specifically one that will interfere with the formation of so-called G-quadruplexes, which occur in many RNA species and may have roles including regulation of translation. The researchers plan to investigate in more depth whether the m7G modification on different RNAs influences other physiological and pathological processes, such as Alzheimer’s disease and liver regeneration. 

This work is the result of an interdisciplinary collaboration calling on diverse expertise, including the mass spectrometry group of the RNA drug company Storm Therapeutics Ltd (Cambridge, UK) and the Department of Chemistry of the University of Cambridge.  

The work was funded predominantly by Cancer Research UK, the Wellcome Trust, the Kay Kendall Leukaemia Fund and the ERC.

 

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Read more about research in the Kouzarides lab.

Watch Tony Kouzarides describe his research on YouTube.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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