VT School of Neuroscience Faculty Recruitment Seminar

Peter Hamilton, Ph.D.
Postdoctoral Fellow
Icahn School of Medicine at Mt. Sinai

  • October 25, 2018
  • 11:10 a.m. – 12:00 p.m.
  • Steger Conference Center (formerly BI)

Long-term drug- or stress-exposure contributes to the pathogenesis of addiction and depression, respectively. These salient experiences impact key brain regions, in part, through epigenetic and transcriptional adaptations, and these adaptations are thought to drive syndrome progression. Pharmacotherapies targeting these molecular adaptations have the potential to combat addiction and depression pathogenesis, yet advances towards this end have been stymied by the lack of causal understanding between the presence of a specific epigenetic modification and its contribution to the larger syndrome. To gain this causal insight, I engineered DNA-targeting tools for neuroepigenetic editing in brain as a means to elucidate the causal mechanisms underlying addiction and depression. To begin applying these tools, our group first characterized the transcriptome of mice resilient to chronic stress. By employing co-expression analysis we identified a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ a novel neuroepigenetic editing approach in the form of CRISPR- mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189- dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience. Interestingly, preliminary data in the nucleus accumbens, a key brain reward region, implicates the CREB-Zfp189 interaction as contributing to stimulant, but not opiate, addiction. In the final portion of my talk, I will present a multi-OMIC analysis of chronically stressed tissue that implicates purine metabolism, fatty acid beta oxidation, and antioxidant pathway function as deferentially contributing to susceptibility or resilience to chronic stress. These molecular networks complement our transcriptional data-sets and are promising targets for manipulation with neuroepigenetic editing tools.

Join on-line from a PC, Mac, Linux, iOS or Android device:

https://virginiatech.zoom.us/j/6407137054

For more information, contact Jonathan Hedrick