Thus far, our discussion has highlighted examples of known cocaine targets that show altered histone modifications or ΔFosB or phospho-CREB binding in our ChIP-chip studies. However, the arrays also provide rich lists of many novel genes, not heretofore implicated in cocaine action, which show robust and highly significant markers of activation or repression in response to chronic cocaine. It was, therefore, important to evaluate the predictive power of these gene lists for revealing fundamentally new insight into the molecular pathophysiology of cocaine action in the NAc. One gene family was of particular interest: the sirtuins. Sirtuins–also referred to as SIRT’s (silent information regulator of transcription)–are categorized as Class III NAD-dependent histone deacetylases, which in addition to deacetylating histones also deacetylate other cellular proteins, such as tubulin, p53 (a tumor suppressor transcription factor), and NFκB (nuclear factor kappa B) (Denu, 2005). Sirtuins are highly conserved from bacteria to mammals–7 forms have been identified in mouse and human–and have been implicated in diverse processes, including cell morphology, growth, apoptosis, general metabolism, and aging (Michan and Sinclair, 2007), although very little is known about their function in the nervous system.
