A-m6A-zing RNA modifications

The newly-emerging field of RNA modification adds another level to the epigenetic control of gene expression.

What determines which genes are turned on and when is a very big question with a lot of possible answers, but one layer of control is epigenetics. Molecular marks on the DNA act as flags to signal to the cell machinery and help determine how any particular gene is regulated. Importantly, these flags can be added and removed, which changes whether genes should be on or off.

RNA is structurally similar to DNA and logically it would seem that similar “epigenetic” marks might also affect how RNA does its job. In fact, it was discovered back in the 1970s that such marks do exist.1,2 Surprisingly though, what these marks do and how they affect RNA regulation, is only just starting to be understood.

The resurgence of interest came about very recently. In 2011, scientists discovered that there is a particular mark found on mRNA – called N6-methyladenosine (or m6A for short) – that can be added and removed.3 In other words, they thought, it could be possible that the presence or absence of this mark might regulate mRNA and how it behaves.

The study identified that a protein, FTO, is an mRNA demethylase that erases the m6A mark from mRNA. FTO was already well known for its association with obesity, but what it actually did was less well understood. Its role in demethylation of mRNA raises the possibility that this may be responsible for its widespread effects on metabolism.

Researchers have also identified a methyltransferase complex, composed of three proteins that is capable of writing m6A marks on the mRNA4,5 as well as one protein that is capable of reading these marks and affecting the stability of methylated transcripts.6

Now that we know that m6A marks can be written, read and erased, scientists can start to investigate what effects they might have on gene expression, cell differentiation, and development.

RNA methylation also has an effect on reproduction. Alkbh5 is turned on more often in testes than other tissues, and both ovary and testis size is affected in animals with disturbed RNA methylation machinery.5,7

Given the central role of mRNA in gene expression, it seems likely that controlling mRNA methylation will play a role in a much wider variety of processes and diseases. This is an exciting new field and there is a lot more to be discovered.

 

References

1Fu et al, 2014, Gene expression regulation mediated through reversible m6A methylation. Nature reviews genetics, 15, 293-306.

2Rottman FM, Desrosiers RC & Friderici K (1976). Nucleotide methylation patterns in eukaryotic mRNA. Prog Nucleic Acid Res Mol Biol, 19, 21-38.

3Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chem Biol, 7, 885–7 (2011).

4Liu J et al. (2014). A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol, 10, 93-5.

5Hongay CF and Orr-Weaver TL (2011). Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. PNAS, 108, 14855-60

6Wang X et al. (2014). N6-methyladenosine-dependent regulation of messenger RNA stability. Nature, 505, 117-120.

7Zheng G et al. (2013). ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell, 49, 18-29.