Files

Abstract

Chemical modifications on RNA play critical roles in gene expression regulation. Although recent advancements have allowed for significant elucidation of their functions, challenges remain in the understanding of their functional effects and the mechanisms involved, and it is becoming increasingly apparent that it is essential to consider the role of the context. Using N6-methyladenosine (m6A) as an example, I explore as a fundamental aspect of context the role of the modification’s location in shaping its function, including the type of RNA on which it is located, its position on the RNA molecule, and the location of the methylated RNA within the cell. First, I present a study characterizing the METTL5-TRMT112 complex which deposits m6A on 18S rRNA. I show that TRMT112 is required for METTL5 stability and that loss of METTL5 regulates gene expression at the translational level, and discuss how the position of the m6A site on 18S rRNA near the decoding center influences its functional roles. Then, I examine the relationship between m6A location and mRNA transcript stability. I show through analysis of public data that m6A in the 5’UTR is associated with increased stability, and that this effect is reduced by depletion of YTHDF2. I further investigate the role of all three YTHDF proteins in transcript stability, revealing that triple knockdown causes extensive transcriptome dysregulation, potentially explained by increased P body formation. In aggregate, this work underscores the importance of location in m6A function, highlighting the necessity of considering a modification’s context to elucidate its cellular function.

Details

Actions

PDF

from
to
Export
Download Full History