Important next steps will be to define the functional relevance of these marks and the precise upstream signals that engage their respective regulatory mechanisms in the brain and to consider these features in a cell-type-specific manner under baseline and activated conditions (Box 1)

Like the epigenetic code surrounding DNA modification, there is also an emergent layer of chemistry that can profoundly influence the life of RNA (Fig. 1). For example, RNA methylation in the form of N6-methyladenosine (m6A) and N1-methyladenosine (m1A) is critical for controlling RNA steady-state levels and even the rate and fidelity of protein synthesis12,13. Another highly abundant RNA modification, pseudouridine (Ψ), has recently been shown to be dynamic and responsive to different stimuli14.

The understanding of the relationship between learning-induced mRNA expression and protein synthesis, and its role in cognition, is currently undergoing a renaissance as novel modes of gene regulation are being integrated into this conceptual framework. For example, epigenetic mechanisms, including DNA methylation and post-translational histone modifications, are involved in driving experience-dependent gene expression underlying the formation and maintenance of memory10,11. These chemical reactions can proceed within microseconds, and chemical modifications of proteins through post-translational modifications can have profound effects on chromatin structure and function and on subsequent gene expression. The rapid modification of cellular macromolecules is therefore highly relevant for activity-dependent molecular processes required for memory formation.