DNA methylation: a permissive mark in memory formation and maintenance

Abstract

DNA methylation was traditionally viewed as a static mechanism required during cell fate determination. This view has been challenged and it is now accepted that DNA methylation is involved in the regulation of genomic responses in mature neurons, particularly in cognitive functions. The evidence for a role of DNA methylation in memory formation and maintenance comes from the increasing number of studies that have assessed the effects of manipulation of DNA methylation modifiers in the ability to form and maintain memories. Moreover, insights from genome-wide analyses of the hippocampal DNA methylation status after neuronal activity show that DNA methylation is dynamically regulated. Despite all the experimental evidence, we are still far from having a clear picture of how DNA methylation regulates long-term adaptations. This review aims on one hand to describe the findings that led to the confirmation of DNA methylation as an important player in memory formation. On the other hand, it tries to integrate these discoveries into the current views of how memories are formed and maintained.

Figure 1.

Hypothetical model for the regulation of hippocampal transcriptional responses during memory formation and maintenance by DNA methylation-dependent mechanisms. Gene transcription activation and de novo protein synthesis are necessary for the formation and maintenance of memory. (1) Following a learning stimulus, an initial transcription wave is induced. The basal epigenetic state of the neuron likely dictates the permissiveness for the activation of the first wave of transcription. For instance, DNA demethylases (such as Tet1 [Rudenko et al. 2013] and possibly others) may be required to hold the promoter and/or enhancer of activity-regulated genes in a hypomethylated state in order to permit rapid activation of transcription. (2) The first wave of transcription includes the up-regulated expression of activity-dependent transcription factors (TFs) (cFos, Npas4, Egr1) and DNA methylation modifiers (Dnmt3a2 (Oliveira et al. 2012), Gadd45b/g (Ma et al. 2009; Leach et al. 2012; Sultan et al. 2012), and possibly others). These TFs and DNA methylation modifiers may work in concert to regulate the expression of downstream effector molecules. (3) In addition to regulating early learning-driven transcriptional responses, DNA methylation players may also modify the epigenome, priming it (4) for later waves of gene expression (for instance, second waves of IEG expression, proposed to be important for memory maintenance), or (5) for responses triggered by subsequent stimulations (such as memory recall or the presentation of a new stimulus). (6) Finally, DNA methylation players, the expression of which are not regulated by neuronal activity, could instead be subject to regulation at the level of activity, stability, or subcellular localization (possibly via post-translational modifications), thus providing for another contribution to the learning-triggered transcription responses and/or epigenome priming. TFs, transcription factors; IEG, immediate early gene.