Novel epigenetic mechanisms in neuronal development and cognitive function

 

Although genetic studies have identified a plethora of MR candidate genes whoseprotein products are implicated in diverse neuronal processes, the regulation mechanisms of these MRcandidate genes remain unclear. Epigenetic regulation has recently emerged as a potentially crucialmechanism in MR. We recently identified and characterized two histone demethylases, SMCX and PHF8,which cause MR when mutated in humans. We showed that the mutant SMCX enzymes found in humanpatients have compromised demethylase activity, indicating the enzymatic activity of SMCX is central to SMCXfunction. We demonstrated that SMCX regulates neuronal cell survival in the zebrafish developing brain anddendritic outgrowth in rat post-mitotic neurons. Recently, we have generated mice carrying a conditional alleleof SMCX. Ablation of SMCX causes deficits in spatial and association memory. One of the main goals of thisapplication is to fully explain the role of SMCX in learning and memory. Specifically, we will determine whetherSMCX plays a general role in all memories or only in a selective set of memory functions. At the cellular level,we will determine whether loss of SMCX impacts neuronal cell survival during mouse brain development anddendritic growth and morphology. Taken together, these experiments will provide a holistic picture of whereSMCX acts in the brain and what memory systems it affects, and whether dendritic morphology regulation is animportant aspect of SMCX function in living animals. Another aim is to understand the mechanisms by whichSMCX regulates cognitive function. We will seek to Identify genome-wide targets of SMCX’s as well as geneexpression network in the cognitive neural circuitry and at critical developmental periods. We will alsoinvestigate how experience such as fear conditioning impacts brain epigenetic landscapes regulated by SMCX.We will carry out genetic complementation experiments to identify SMCX-regulated direct genes that mediateSMCX’s effect in fear conditioning response. We will test our hypothesis that SMCX regulates gene expressionby controlling both promoter activity and neuronal enhancer function where it may contribute to the formation ofH3K4me1, a hallmark histone modification for enhancers, whose genesis is currently unknown. Finally we willcarry out proteomics experiments to identify SMCX associated proteins in the brain, whose identity will helprefine our model of how SMCX may collaborate with other chromatin modifying enzymes to shape the neuronalepigenomes and to regulate learning and memory. Taken together, findings will provide significant new insightsinto epigenetic mechanisms that control cognitive function and behavior, which, when gone awry, can causedebilitating human disease such as intellectual disability. Findings will be relevant to additional mentaldisorders since patients with SMCX mutations may also suffer from epilepsy, aggression, and/or autism.