Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex

Amanda C. Mitchell, Behnam Javidfar, Lucy K. Bicks, Rachael Neve, Krassimira Garbett, Sharon S. Lander, Karoly Mirnics, Hirofumi Morishita, Marcelo A. Wood, Yan Jiang, Inna Gaisler-Salomon and Schahram Akbarian ()
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Amanda C. Mitchell: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Behnam Javidfar: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Lucy K. Bicks: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Rachael Neve: McGovern Institute for Brain Research, Massachusetts Institute of Technology
Krassimira Garbett: Vanderbilt University
Sharon S. Lander: University of Haifa
Karoly Mirnics: Vanderbilt University
Hirofumi Morishita: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Marcelo A. Wood: University of California at Irvine
Yan Jiang: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Inna Gaisler-Salomon: University of Haifa
Schahram Akbarian: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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 GmethylATC 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.

Date: 2016
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DOI: 10.1038/ncomms12743

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