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Nat Commun. 2016 Sep 6;7:12743. doi: 10.1038/ncomms12743.

Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex.

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Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
McGovern Institute for Brain Research, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, Massachusetts 02139, USA.
Department of Psychiatry, Vanderbilt University, 1211 Medical Center Drive, Nashville, Tennessee 37232, USA.
Department of Psychology, University of Haifa, 199 Aba Khoushy Avenue Mount Carmel, 3498838 Haifa, Israel.
Department of Neurobiology and Behavior, University of California at Irvine, 2205 McGaugh Hall, Irvine California 92697, USA.


Neuronal epigenomes, including chromosomal loopings moving distal cis-regulatory elements into proximity of target genes, could serve as molecular proxy linking present-day-behaviour to past exposures. However, longitudinal assessment of chromatin state is challenging, because conventional chromosome conformation capture assays essentially provide single snapshots at a given time point, thus reflecting genome organization at the time of brain harvest and therefore are non-informative about the past. Here we introduce 'NeuroDam' to assess epigenome status retrospectively. Short-term expression of the bacterial DNA adenine methyltransferase Dam, tethered to the Gad1 gene promoter in mouse prefrontal cortex neurons, results in stable G(methyl)ATC tags at Gad1-bound chromosomal contacts. We show by NeuroDam that mice with defective cognition 4 months after pharmacological NMDA receptor blockade already were affected by disrupted chromosomal conformations shortly after drug exposure. Retrospective profiling of neuronal epigenomes is likely to illuminate epigenetic determinants of normal and diseased brain development in longitudinal context.

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