N6-methyladenosine in poly(A) tails stabilize VSG transcripts

Idálio J. Viegas, Juan Pereira Macedo, Lúcia Serra, Mariana De Niz, Adriana Temporão, Sara Silva Pereira, Aashiq H. Mirza, Ed Bergstrom, João A. Rodrigues, Francisco Aresta-Branco, Samie R. Jaffrey and Luisa M. Figueiredo ()
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Idálio J. Viegas: Universidade de Lisboa
Juan Pereira Macedo: Universidade de Lisboa
Lúcia Serra: Universidade de Lisboa
Mariana De Niz: Universidade de Lisboa
Adriana Temporão: Universidade de Lisboa
Sara Silva Pereira: Universidade de Lisboa
Aashiq H. Mirza: Cornell University
Ed Bergstrom: University of York
João A. Rodrigues: Universidade de Lisboa
Francisco Aresta-Branco: Universidade de Lisboa
Samie R. Jaffrey: Cornell University
Luisa M. Figueiredo: Universidade de Lisboa

Nature, 2022, vol. 604, issue 7905, 362-370

Abstract: Abstract RNA modifications are important regulators of gene expression1. In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally2. N6-methyladenosine (m6A) has been detected in this parasite, but its function remains unknown3. Here we found that m6A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m6A is located in the poly(A) tail of the actively expressed VSG transcripts. m6A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m6A in the poly(A) tail and a 16-mer motif in the 3′ untranslated region of VSG genes. Using genetic tools, we show that the 16-mer motif acts as a cis-acting motif that is required for inclusion of m6A in the poly(A) tail. Removal of this motif from the 3′ untranslated region of VSG genes results in poly(A) tails lacking m6A, rapid deadenylation and mRNA degradation. To our knowledge, this is the first identification of an RNA modification in the poly(A) tail of any eukaryote, uncovering a post-transcriptional mechanism of gene regulation.

Date: 2022
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DOI: 10.1038/s41586-022-04544-0

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