Synapse communication with the epigenome

Memory consolidation is known to occur when short-term memory traces in the hippocampus are transferred to long-term storage areas in the cortex, over a period of ~ 1 week. Now Lesburguères et al have published a very interesting study looking at the mechanism of this transfer in rats, showing (by inhibiting various processes) that it is dependent upon epigenetic changes (specifically, histone acetylations) in the olfactory cortical neurons that are “tagged” with the memory for that smell. This process is also dependent upon synaptic activation, indicating that there is some sort of way that synaptic signals communicate with the epigenome of the cell, and determining those mechanisms will likely be very enlightening.

This is just one of a slew of recent papers emphasizing the importance of epigenetics in cellular regulation, and I have officially jumped on the bandwagon. For example, John et al’s recent paper shows the importance of chromatin’s accessibility state to the “de novo” DNA binding patterns of the glucocorticoid receptor, a model transcription factor. They found that chromatin’s accesibility state explained much more variance in the transcription factor binding activity than the intergenic DNA binding motifs. Nature Genetics is not OA so I can’t post it here, but do look at their fig 3 showing the correlation between glucocorticoid receptor CHiP-Seq and DNase-seq, which is staggeringly high.

One of the reasons epigenomics holds great promise is that it seems much more “decodable” than the protein, lipid, or RNA landscape of a living cell. For example, see recent technologies to probe the cytosine methylation, nucleosome positioning, or various histone modifications. Of course histones can undergo many post-translational modifications, but one at a time is a start and eventually some sort of multi-antibody system might co-immunoprecipitate many types of them, or some other method entirely could decode the histone modification landscape.

Indeed, one can imagine a future technology that would first determine the position of neurons and glial cells, then characterize the neurons’ post- and pre-synaptic densities, and then “sequence” their epigenomes; such information might be able to reproduce a lot of the function of that network.

References

Lesburguères et al, 2011. Early Tagging of Cortical Networks Is Required for the Formation of Enduring Associative Memory. Science. doi: 10.1126/science.1196164.

John et al, 2011. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nature Genetics doi:10.1038/ng.759.

Lister R et al, 2008. Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis. Cell doi:10.1016/j.cell.2008.03.029.

Zhang Z et al, 2011. High-Resolution Genome-wide Mapping of the Primary Structure of Chromatin. Cell doi: 10.1016/j.cell.2011.01.003.

Maze I et al, 2010. Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity. Science doi: 10.1126/science.1179438.