Epigenetics in Neurobiology and Neural Disease
Epigenetics is the study of heritable chromatin regulatory mechanisms that determine the transcriptional state of genes in the genome. The molecular marks that define these regulatory pathways include DNA methylation, as well as a large range of posttranslational modifications of the histone proteins that wind DNA into nucleosomes, the functional unit of chromatin.  Epigenetic mechanisms are crucial for restricting the totipotency of cells during development and differentiation, however the fact that these same molecular pathways can be regulated by extracellular stimuli raises the possibility that, in the nervous system, epigenetic transcriptional mechanisms may also play a role in long-lasting synaptic plasticity and persistent behavioral adaptations.
           
The epigenetic code is read and translated into transcriptional outcomes by the local recruitment of proteins that bind to methylated DNA and modified histones. Our current projects focus on the methyl-DNA binding transcriptional repressor MeCP2. Loss-of-function mutations in MeCP2 cause the human neurodevelopmental disorder Rett Syndrome, which has been proposed to result from abnormal synaptic development during postnatal life. Intriguingly, neuronal activity leads to phosphorylation of MeCP2 at a site that is required for activity-dependent transcriptional derepression of the Bdnf gene. These data suggest that one key function of MeCP2 in the brain may be to link neuronal activity with the transcription of gene products like Bdnf that regulate synaptic development and plasticity.

To study how epigenetic regulation of gene transcription may contribute to behavior, we are examining the role of MeCP2 and other epigenetic transcriptional repression mechanisms in neural responses to cocaine and other drugs of abuse. Alterations in gene expression contribute to the synaptic adaptations of brain reward circuits that underlie persistent drug sensitization behaviors. We hypothesize that MeCP2 regulates cocaine-induced transcriptional programs, and that the regulation of repressive histone methylation contributes to the development of drug sensitization behaviors. We are testing this hypothesis by combining biochemical analyses of cocaine-dependent regulation of MeCP2 and histone methylation with experimental manipulation of these processes in mouse models. These studies will fill a critical gap in knowledge by defining new mechanisms that contribute to the effects of cocaine on both neuronal gene expression and behavior and may reveal new targets for therapies in the treatment of drug addiction.

We use transfection of low density neuronal cultures to study how gene manipulation in single cells affects the process of synapse formation.
The image above shows a GFP-transfected neuron (green) grown in culture on a bed of underlying glial cells (labeled for GFAP in blue). Synapses are labeled for synapsin I (red).