Memories; we all have some we would rather forget, and some that we will hold onto forever. But how exactly is memory formed and what are the biochemical pathways that are in play? Recent studies have indicated that RNA and DNA adenosine methylation are important for the conversion of experiences, both good and bad, into long-term memory. So, hey methylation, thanks for the memories!
m6A RNA Methylation and the Conversion of Experience into Memory
N6-methyladenosine (or m6A) is one of our favorite RNA modifications here at EpiGenie, where we have discussed m6A-mediated regulation of both embryonic stem cell pluripotency and differentiation, heat shock responses, and even obesity. We also know that the m6A modification enhances mRNA stability, is prevalent in the mouse brain, and increases in abundance as mice age (Meyer et al., 2012). This has led some to hypothesize that experience itself can regulate m6A levels.
In a memorable new study, researchers from the groups of Timothy W. Bredy and Jocelyn Widagdo (University of Queensland, Australia) have now found strong evidence for the m6A modification of RNA in the conversion of experience into memory.
This new study mapped genome-wide m6A levels via methylated RNA immunoprecipitation (MeRIP-seq) in brain tissue (the prefrontal cortex to be specific!) derived from mice undergoing fear-based memory conditioning. Overall, the researchers found:
- An increase in neuronal m6A levels in response to fearful experiences
- m6A enrichment occurred at the stop codon of mRNAs coding for neuronal plasticity genes (aha!) and enhanced the stability of some mRNAs
- Increased m6A levels correlated to an increase in Mettl3 RNA methyltransferase expression and Fto RNA demethylase repression
- Fto-knockdown using a short hairpin RNA increased global m6A levels and led to a significant increase in fear memory
So if our memory serves us well, it seems that that experience of fear leads to the accumulation of m6A levels on RNA which serves to aid memory and behavioral adaptation. So before you forget, get over to the Journal of Neuroscience, June 2016, to say thanks for the memories!
More Methylation in Memory; Don’t Forget DNA
But wait, I nearly forgot (my m6A levels must be lacking), there is more! The next study is also from the laboratory of Timothy W. Bredy, but this time (via a bioRxiv pre-print) they describe a link between a new DNA modification and memory formation.
The DNA modification in question is the newly discovered N6-methyl-2-deoxyadenosine (m6dA), whose accumulation leads to increased gene expression in lower eukaryotes. This new study now demonstrates that m6dA accumulation on DNA promotes activity-induced gene expression in the adult brain and helps the formation of fear extinction memory in mice.
This new study found that:
- m6dA is a dynamic and prevalent modification in the mouse brain mediated by the N6amt1 adenine methyltransferase
- In activated primary cortical neurons, m6dA accumulates at the promoter of brain-derived neurotrophic factor (bdnf), a gene known to nurture learning and memory
- m6dA accumulation promoted mRNA expression via active chromatin state formation and transcriptional machinery recruitment
- Knockdown of N6amt1 blocked m6dA accumulation, inhibited active chromatin state formation and transcriptional machinery recruitment, and reduced bdnf expression
- The authors also corroborated the above in vitro findings by going to the mouse brain (the prefrontal cortex yet again!)
- fear extinction learning events boosted levels of N6amt1-mediated m6dA at the bdnf promoter
- Knock-down of N6amt1 significantly blocked fear extinction memory
So now we have proof for DNA and RNA adenosine methylation in the formation of memory, but a few lingering questions lie tantalizingly unanswered. These include whether a potential mechanistic link between DNA and RNA adenosine methylation during memory formation exists, whether modifications such as m6dA have functions beyond memory formation, and finally, whether other modifications, both on DNA and RNA, lie unstudied, begging to be understood?!