Modification of mRNA by snoRNA-guided 2 '-O-methylation

Post‐transcriptional modifications of messenger RNA (mRNA) are emerging as an important layer of regulatory control over gene expression. Base modifications, especially N 6 ‐methyladenosine (m 6 A), influence mRNA splicing, stability, and translation by altering base‐pair interactions and recruiting or inhibiting RNA‐binding proteins. While there is evidence that internal ribose modification by 2′‐ O ‐methylation (Nm) also occurs on mRNA, questions have been raised regarding its detection, and no biological role has been validated for this modification in cells or tissues. Here we show that internal 2′‐ O ‐methylation of mRNA serves as a new mechanism of genetic regulatory control, with the ability to influence mRNA abundance and protein levels, both in vitro and in vivo . Using genetic models, we show that this requires: (1) small nucleolar RNAs (snoRNAs), and (2) the snoRNA‐guided 2′‐ O ‐methylase ( fibrillarin, Fbl ). Since there are hundreds of box C/D snoRNAs (SNORDs) that can guide Nm modifications, snoRNA‐guided modification of mRNA could be a widespread mechanism of post‐transcriptional gene regulation. Overall, these findings show that SNORDs guide 2′‐ O‐ methylation of mRNA, and that Nm can provide a significant post‐transcriptional regulatory mechanism to regulate physiologic gene expression in vivo . Support or Funding Information The following funding sources supported this work: NIH K08HL114889, R03HL135475, and Duke Heart Center Junior Faculty Development Award to C.L.H., AHA 14POST20380015 and NIH T32HL7101‐42 to B.A.E., and AHA 16POST27540007 to H.H. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .