Arturas Petronis, CAMH, Toronto, Canada
Moshe Szyf, McGill University, Montreal, Canada
Scharahm Akbarian, University of Massachusetts Medical School, Worcester, USA
Dennis R. Grayson, University of Illinois at Chicago, USA
Hongjun Song, Johns Hopkins University, Baltimore, USA
Michael J. Meaney, McGill University, Montreal, Canada
Janine LaSalle, University of California, Davis, USA
Andre Fischer, European Neuroscience Institute, Göttingen, Germany
The term epigenetics refers to DNA methylation changes and covalent chromatin modifications that persist from one stage of cell division to the next stage in dividing germ lines, somatic, and cancer cells. The epigenome also undergoes covalent modifications in post-mitotic neurons in response to neuropathological factors, environmental influences, or drug exposure. However, in differentiated post-mitotic neurons, activity-dependent chromatin remodeling events are specific for different neuron subtypes and may be transient. Hence, in the adult brain, the reported specificity of chromatin remodeling for different subsets of genes suggests that the rules governing neuroepigenetic changes in differentiated neurons may be different from the rules governing epigenetic mechanisms in cells that undergo division. Unlike in somatic cells, an understanding of the mechanistic details of chromatin remodeling events in post-mitotic neurons is only just beginning to be understood. However, tremendous progress has been made recently in neuroepigenetics leading to a better understanding of the role of DNA methylation, histone modifications, and siRNAs in regulating gene expression and brain function.
Population, family, and twin studies indicate that psychiatric disorders are highly heritable. However, the association of single alleles that confer increased risk has only been confirmed in a small proportion of observed phenotypic variants. Hence, the hypothesis that major psychiatric disorders can be attributed to a relatively few common genetic variants has been questioned. Rather, it appears that these disorders are the consequence of synergistic interactions of multiple susceptibility genes with neuroepigenetics factors such as drugs, stress, or other environmental influences that act on neuronal chromatin altering gene transcription without changing the DNA sequence.
Critical discussion during the Course will focus on evidence suggesting that neuroepigenetics may play an essential role during brain development and in brain disorders, including multiple brain functions such as learning and memory, drug addiction, neurodegeneration, and responses to stress. Altered neuroepigenetic mechanisms have been directly implicated in the pathogenesis of several psychiatric disorders, including autism, fragile X syndrome, Rett syndrome, schizophrenia, bipolar disorder, suicide, and depressive disorders.
Pharmacological intervention using findings along these research lines are coming close. Drugs such as histone deacetylase inhibitors known to alter epigenetic processes are increasingly being considered for the treatment of psychiatric disorders and a better understanding of the molecular mechanisms underlying epigenetic changes in psychiatric or neurological disorders will likely lead to the development of safer and more potent pharmacological agents specifically targeted to the neuroepigenome.
The Course will present many cutting edge findings and methodological approaches in the field and will be a forum for the discussion of topics from basic neuroepigenetic mechanisms to the pathogenetic processes underlying psychiatric and neurological disorders. Considering the exponential growth of the field and the quality of the speakers, it is anticipated that the advancement in understanding mechanisms regulating chromatin remodeling in diseases of the brain will provide new insights into the underlying neurobiological causes of these disorders.
Importantly, the Course will provide an intellectual forum designed to increase each participant's knowledge regarding the latest findings in the new field of neuroepigenetics. Informal interactions between participants and faculty will provide the inspiration to impact future research and teaching activities extending beyond the meeting as participants pursue careers in neuroscience, medicine and drug discovery.
Topics that will be discussed include:
1. Mechanisms that facilitate chromatin remodeling in the activation or repression of gene expression in different neuronal subtypes (e.g., GABAergic interneurons, glutamatergic principal neurons) vs glial cells
2. The role of siRNAs in neuroepigenetics.
3. The issue of whether altered patterns of DNA methylation in brain disorders are the result of changes in the levels or activities of DNA methyltransferases or enzymes that facilitate DNA demethylation or both.
4. The relevance of alterations in chromatin modifying enzymes to cognitive function in health and disease.
5. Identification of specific histone modifications and aberrant methylation of candidate gene promoters in schizophrenia, depression, bipolar disorder, autism spectrum disorders, and in subjects exposed to stressful experiences, especially early in life.