It’s no secret that microRNAs are pretty busy molecules. A single microRNA can regulate the expression of several, maybe even hundreds, of transcripts. If that wasn’t enough, researchers at the Chinese Academy of Sciences, Beijing now add another function to this packed list of duties: the control of m6A RNA methylation, which is emerging as an important regulator of cell fate and differentiation.
If you are an epigenetics enthusiast you likely have already heard about m6A RNA methylation. Much like DNA methylation, m6A has enzymes that establish it (METTL3 and METTL14) and erase it (FTO and ALKBH5) on mRNA. This modification has been implicated in just about every aspect of mRNA metabolism. However, we still know surprisingly little about its importance on a global scale.
All this is about to change though with recent improvements to m6A-seq technology, which are enabling researchers to explore the landscape of m6A in different cell types. This technology has already been put to good use in embryonic stem cells, to reveal an important role for m6A in the control of cell fate decisions. Now, Qi Zhou and his team have created transcriptome-wide maps of m6A in four different cell types at various stages of differentiation.
Among other things, Zhou and colleagues used these new maps to answer a burning question: how is m6A regulated? After some careful data mining and some clever gain- and loss-of-function experiments they soon had their answer:
- A staggering 92–96% of sequences enriched in m6A (‘m6A peaks’) overlapped with binding sites for microRNAs.
- Overexpression of microRNAs pairing with randomly selected m6A peak regions led the accumulation of m6A at these regions.
- Mutation of microRNAs created new binding regions on transcripts previously devoid of m6A peaks.
Thus, microRNAs appear to control m6A methylation. By tinkering with the expression of microRNAs through the knockdown of Dicer or the use of antagomirs, the team even manage to show how this is achieved: microRNAs control the interaction between METTL3 and mRNA.
Going further, they examine the function of m6A in cell fate decisions and find that METTL3 overexpression in mouse embryonic fibroblasts promotes the accumulation of m6A and improves the efficiency of induced reprogramming to pluripotency.
So if you are feeling overworked, just think of all the responsibilities of microRNAs and head on over to Cell Stem Cell, February 2015.