When it comes to post-translational modifications, it’s fair to say that DNA and proteins have taken most of the limelight in epigenetics. RNA modifications have been largely relegated to the role of supporting actor. Not content with nucleosomes taking all the credit, a team of Stanford and Harvard researchers now demonstrate the importance of RNA methylation in cell fate transitions.
More than 100 modifications have been identified in cellular RNAs. The most common mark on messenger RNA is N6-methyl-adenosine (m6A). Like modifications to histones and DNA, this mark is reversible: METTL3 (and the recently discovered METTL14) write m6A marks, whereas the demethylases FTO and ALKBH5 erase them. m6A has been implicated in almost all aspects of mRNA metabolism, buts its influence on gene expression programs is poorly understood.
Batista and coworkers mapped the m6A methylome in mouse and human embryonic stem cells (ESCs) and examined changes to m6A during differentiation.
Here’s what they found:
- m6A is common in both mESCs and hESCs and its targets are highly conserved (58% overlap between the two datasets).
- m6A targets many pluripotency factors and genes dynamically regulated during differentiation.
- Transcripts marked with m6A show a high rate of decay.
Mouse ESCs completely lacking Mett3l were viable and showed strong self-renewal. They also failed to differentiate correctly and hESCs deficient in METT3L showed similar defects.
Thus, insufficient m6A blocks ESC differentiation and promotes a highly proliferative, stem-like state.
Sound familiar? Cells lacking DNA methyltransferases also fail to differentiate; however, in contrast with DNA methylation, m6A may act to counteract epigenetic fidelity and promote transcriptome flexibility.
Self-renewal in ESCs must be rapidly switched off following differentiation signals and m6A may mark stem cell transcripts for degradation to facilitate the transition between different states. As Batista puts it, m6A helps cells “to forget the past and embrace the future”, and may play a similar role during other transitions in gene expression programs.
Learn more about the ‘anti-epigenetic’ potential of m6A in Cell Stem Cell, October 2014.