The lab’s over-arching goal is to understand the epigenetic mechanisms behind transcriptional regulation and chromatin structure in mammals. A major focus is the study of mechanisms that regulate the expression of neuronal target genes. We have shown that the transcription factor NRSF recruits a number of chromatin modifying complexes that include histone deacetylases and methylases. Also, we have found that NRSF uses a metabolism-sensing co-repressor to repress expression of genes involved in nervous system function as well as tumor metastasis.
Based on these findings, we have been able to control genes important for the progression of epilepsy in vivo by the use of small molecule inhibitors of glycolysis. This treatment resulted in suppression of epileptogenesis in rodent models of epilepsy and our small molecule inhibitors of energy metabolism will be entering clinical trials for epilepsy in the coming months.
Many genes regulated by NRSF are implicated in metastasis. As such we are pursuing the possibility of controlling genes important for cancer progression using small molecule regulators of energy metabolism. These projects span both neuroscience and cancer biology and have generated compounds that can go into clinical trials for neurological disorders and metastasis prevention.
- Localized domains of G9a mediated histone methylation are required for silencing neuronal genes. Roopra, A., Qazi, R., Schoenike, B., DaleyT.J., Morrison, J.F. Mol. Cell (2004) 14(6): 727-38.
- 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure Mireia Garriga-Canut, Barry Schoenike, Romena Qazi, Karen Bergendahl, Timothy J. Daley, Rebecca M. Pfender, John F. Morrison, Jeffrey Ockuly, Carl Stafstrom, Thomas Sutula, and Avtar Roopra. Nat. Neuroscience, 9(11), 1382-1387, 2006.
- REST is lost in aggressive breast cancer. Matthew Wagoner, Kearney Gunsalus, Andreas Freidl, Andrea Richardson, Avtar Roopra. PloS Genetics, 6(6), e1000979, 2010. PMCID: PMC2883591
- Metabolic regulation of neuronal plasticity by the energy sensor AMPK. Wyatt B. Potter, Kenneth J. O’Riordan, David Barnett, Susan M.K. Osting, Matthew Wagoner, Corinna Burger, Avtar Roopra. PLoS ONE, 5(2) e8996, 2010. PMCID: PMC2813866
- Reduced Juvenile Long Term Depression in Tuberous Sclerosis Complex is Mitigated in Adults by Compensatory Recruitment of mGluR5 and Erk Signaling. Wyatt B. Potter, Kenneth J. O’Riordan, Allison Kirchner, Paul Rutecki, Corinna Burger, Avtar Roopra. PLoS Biology, 11(8), e1001627, 2013. PMCID: PMC3742461