DNA methylation based binary enhancers govern neuronal allocation to coding in the hippocampus

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Abstract Experiences are coded by small ensembles of recruited neurons in the hippocampus. Although multiple neurons receive a stimulus, only a subset of them is “allocated” to encode a given memory. It has been shown that neurons with higher levels of intrinsic excitability are preferentially recruited during context exposure, yet the principles governing neuron recruitment are not known. Neuron allocation has medical relevance, as it is the first step in memory formation and thus may be targeted to mitigate cognitive deficits associated with aging and Alzheimer's disease and other neurodegenerative disorders. Here we introduce a model that, via DNA methylation based binary enhancers may explain neuron allocation in the hippocampus. Specifically, we identified thousands of small genomic regions that in some cells exist in fully methylated, and in others, in fully unmethylated states, in contrast to the surrounding genome, which is uniformly methylated or unmethylated in all neurons. Since these regions are embedded in synaptic genes and have a DNA methylation dependent transcription-enhancing effect, they can be conceptualized as DNA methylation based bistable enhancers regulating neuronal/synaptic activity. We propose that the identified neuronal enhancers alternate between the “methylated” and “unmethylated” positions, and that this provides, at any given time, a small (sparse) but sufficient population of neurons with specific constellations of unmethylated and methylated switches that is eligible for allocation to code experiences. The goal of this application is to test the role of the identified epigenetically bistable DNA sequences in neuron allocation. We will 1) determine the allocation epigenetic code by sequencing the methylome of allocated neurons, 2) test the functional link between bistable enhancers and neuron allocation, and 3) assess if epigenetic malleability of enhancers contributes to environment-induced changes in cognitive functioning. The premise of our model is that it provides, through epigenetic switching, a combinatorial- molecular mechanism for the elusive process of neuron allocation and sparse/segregated population coding of experiences. Furthermore, the sensitivity of DNA methylation based switches provides an opportunity for their selective manipulation to improve neuron allocation and encoding in cognitive disorders.