, 2010b). Thus, active regulation of epigenetic marks in a neuron must exist simultaneously alongside the

stable epigenetic marks that perpetuate neuronal phenotype over the lifespan. How can a single genome be subject to both perpetual and immutable epigenetic marking at the same time it is subject to dynamic regulation in response to experience? This thought experiment tells us that some set of mechanisms must compartmentalize the developmental epigenome from the dynamic epigenome. These mechanisms are completely mysterious at present. As described in the introductory section, epigenetic mechanisms are so powerful because they can self-perpetuate over time. Indeed, this peculiar aspect of epigenetics is why Francis Crick first proposed DNA methylation as a component of memory storage in the nervous system in a personal correspondence find protocol to the editor at Nature ( Crick, 1984). However, as described above, self-perpetuating epigenetic mechanisms are not limited to DNA selleck chemicals modifications—prion-like mechanisms, histone subunit exchange, and histone methylation all have the demonstrated, or at least hypothetical, capacity for self-regeneration in the face of protein turnover. Presumably, other self-reinforcing protein-based mechanisms await discovery,

and their potential roles in neuronal information storage are tantalizing. My final question for this perspective piece is whether, as scientists, we will ever be able to fully comprehend the mechanistic roles of neuroepigenetic mechanisms

in any sort of compelling, understandable, and satisfying fashion. It might be a reality that the neuroepigenetic mechanisms operating in the CNS are so complex that they defy comprehensive explanation and understanding. I certainly hope this is not the case! But as a closing comment, I would like to explain my fear in this regard. Explaining how neuroepigenetic mechanisms serve ever as the interface between genes and experience, or nature and nurture as I mentioned to start this essay, is certainly going to be a big data endeavor. It is already clear that tracking epigenetic changes in the CNS over the lifespan is going to be a huge bioinformatics challenge (Lister et al., 2013). The biomedical poster child for big data thus far has been sequencing the human genome, as well as the genomes of other species. This is the prototype for how we think about large-scale bioinformatics initiatives in biology: sequencing and annotating the 3 billion or so nucleotides comprising a mammalian genome. However, the genome in all its complexity is simply the basic first layer of infrastructure upon which epigenetic mechanisms operate. A single mammalian organism has a single genome, but that same organism has hundreds of cellular phenotypes, each of which has its own distinct epigenome.