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Schahram Akbarian, Ph.D.,M.D.

Epigenetics and the Brain

Epigenetic marks, including cytosine methylation of genomic DNA and a rich cache of post-translational modifications of nucleosome core histones, could provide a type of cellular memory, and potentially maintained for the remainder of a cell's life and transmitted to daughter cells.  Furthermore, evidence is accumulating that there is epigenetic heritability across generations in human, at least in principle. Therefore, the general theme of epigenetics is of great interest to the field of biological psychiatry because (i) it could provide valid and testable alternatives to genetic heritability models and (ii) exploration of chromatin structure and function in healthy and diseased brain could provide novel insights into the pathophysiology of major psychiatric disease. The primary focus of our laboratory is on the exploration of neuronal epigenomes in preclinical model systems and in human (postmortem) brain tissue. The following example highlights an ongoing research project:

Chromatin Alterations in Developing and Diseased Prefrontal Cortex

Prolonged maturation of prefrontal cortex (PFC), extending into or even beyond the second decade, plays a key role for normal human development and the neurobiology of schizophrenia, mood spectrum disorders and other disease. Contemporary neurobiological models explaining the protracted maturation of prefrontal and other higher order association areas of the human cerebral cortex-such as (i)  changes in supply and expression of certain neurotrophic factors; or (ii) increased axon fiber myelination, or (iii) synaptic pruning- in essence date back more than 20 years, and only few advancements have been made since then. Moreover, many of these hypotheses are built on correlative observations and there is little evidence for causality. Because a number of neuronal genes undergo progressive histone lysine methylation during early childhood years, changes in neuronal chromatin structure and function, in conjunction with transcriptional regulation, could take part in a molecular "clock" operating during an extended period of PFC development, thereby regulating the protracted maturation of its neuronal circuitry. These may involve dynamic adaptations of site-specific histone lysine methylation markings that are thought to contribute to epigenetic control of gene expression. We approach this topic by genome-wide mapping of  histone methylation landscapes in prefrontal neurons: (1) across the lifespan to understand normal development and aging; (2) in subjects on the psychosis or autism spectrum in order to gain insight into mechanisms of disease; (3) in genetically engineered mice with brain-specific ablation, or siRNA-mediated knockdown, of selected histone methyltransferase and demethylase enzymes that specifically target the histone H3-lysine 4 residue which is highly regulated at enhancer sequences and transcription start sites (see Figure).

Phone: 508-856-2926
E-mail: Schahram.Akbarian@umassmed.edu
Keywords: Genetic Systems, Neurobiology

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