N 6 -methyladenosine in poly(A) tails stabilize VSG transcripts

• Published in: Nature (London) 2022-04, Vol.604 (7905), p.362
• Main Authors: Viegas, Idálio J, de Macedo, Juan Pereira, Serra, Lúcia, De Niz, Mariana, Temporão, Adriana, Silva Pereira, Sara, Mirza, Aashiq H, Bergstrom, Ed, Rodrigues, João A, Aresta-Branco, Francisco, Jaffrey, Samie R, Figueiredo, Luisa M
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Adenosine - analogs & derivatives; Gene Expression Regulation; RNA - metabolism; RNA Processing, Post-Transcriptional; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription, Genetic; Trypanosoma brucei brucei - genetics; Variant Surface Glycoproteins, Trypanosoma - genetics
• ISSN: 1476-4687
• DOI: 10.1038/s41586-022-04544-0

RNA modifications are important regulators of gene expression . In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally . N -methyladenosine (m A) has been detected in this parasite, but its function remains unknown . Here we found that m A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m A is located in the poly(A) tail of the actively expressed VSG transcripts. m A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m A 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 m A in the poly(A) tail. Removal of this motif from the 3' untranslated region of VSG genes results in poly(A) tails lacking m A, 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.