As illustrated

in the list in Table 2, this is an extremely broad question, and obviously I cannot discuss it in detail in a brief commentary such as this. However, I will note that epigenetic mechanisms may be particularly relevant to multifactorial diseases with low genetic penetrance, such as schizophrenia and depression (Petronis, 2010). Thus, epigenomically based mechanisms for these disorders may help fill a void where, historically, genomic analyses have not led to clearly identifiable causes. In addition, disorders that are triggered by just one or only a few experiences, but that are henceforth enduring, also seem likely candidates to be epigenetically mediated. In this line of thinking, disorders such as drug addiction, posttraumatic stress disorder (PTSD), epilepsy, and schizophrenia might selectively MK-2206 cell line involve the cooptation of epigenetic mechanisms used for development and learned behavior to subserve behaviorally disadvantageous, but obdurate, behavioral change. This is the corollary to the preceding question—if epigenetic mechanisms are broadly involved in CNS disorders,

might epigenetic targets as a category be broadly applicable to drug development? This is a very active area of investigation at present, with drug discovery efforts OSI-744 manufacturer ongoing in the areas of cognitive enhancers for learning disabilities, Alzheimer’s disease, neurodegenerative disorders, schizophrenia, depression, addiction, generalized stress disorders, and PTSD (Kazantsev and Thompson, 2008, Fischer et al., 2007, Anier et al., 2010, Kilgore et al., 2010, Peleg et al., 2010, Renthal and Nestler, 2008, Szyf, 2009, Monsey et al., 2011 and Oliveira et al., 2012). Some aspects of this question are among the most contentious areas in the epigenetics field at present. Broadly speaking, epigenetic transgenerational effects come in two flavors. The first type is not transgenerational in the heritable sense, but rather is experience dependent. For example, Michael Meaney’s group, his collaborators, and scientific

descendants have demonstrated that maternal nurturing behavior regarding newborn pups triggers DNA methylation changes in CNS glucocorticoid receptors of offspring not that persist into the adult and effect behavioral change (Champagne and Curley, 2009, Weaver et al., 2004 and Weaver et al., 2005). Discovery of these experience-dependent changes in the epigenome is the prototype for the first category of transgenerational effects, and such experience-driven epigenomic changes in the CNS have been documented to occur with a number of both positive and negative environmental effects in offspring. Thus, several examples of the persisting CNS epigenomic effects on offspring of parental behavior and environmental insult have survived the rigors and skepticism of peer review (Champagne and Curley, 2009 and Roth et al., 2009).