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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).

Figure

Representative Publications

Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S (2007) Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. Journal of Neuroscience 27: 11254-11262.  PMID: 17942719

Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S (2007) DNA methylation in the human cerebral cortex is dynamically regulated across the life span and involves differentiated neurons. PLoS ONE: e895.  PMID: 17878930

Schroeder FA, Pental KL, Matevossian A., Jones SR, Konradi C, Tapper AR, Akbarian S (2008) Drug-induced activation of dopamine D1 receptor signaling and inhibition of class I/II histone deacetylase induces chromatin remodeling in reward circuitry and modulates cocaine-related behaviors. Neuropsychopharmacology 33:2981-2992.

Jiang Y, Matevossian A, Huang HS, Straubhaar J, Akbarian S (2008) Isolation of neuronal chromatin from brain tissue. BMC Neuroscience 9:42.  PMID: 18442397

Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S (2008) A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Human Molecular Genetics 17: 3030-3042.  PMID: 18632683

Jiang Y., Langley B., Lubin F.D., Renthal W., Wood M.A., Yasui D.H., Kumar A., Nestler E.J., Akbarian S., Beckel-Mitchener A.C. (2008) Epigenetics in the nervous system. Journal of Neuroscience 28: 11753-11759.  PMID: 19005036

Mellios  N, Huang HS, Galdzicka M, Ginns E, Akbarian S (2009) Molecular determinants of dysregulated GABAergic gene expression in schizophrenia. Biological Psychiatry 65:1006-1014.

Matevossian A., Akbarian S. (2008) A chromatin assay for human brain tissue. Journal of Visualized Experiments 13: pii: 7171. doi: 10.3791/717.

Akbarian S, Huang HS (2008) Epigenetic regulation in human brain - focus on histone lysine methylation. Biological Psychiatry 65: 198-203.

Matevossian A., Akbarian S. (2008) Neuronal nuclei isolation from human postmortem brain tissue. Journal of Visualized Experiments 20: pii:914. Doi:10.3791/914.

Akbarian S (2008) Restoring neuronal synchrony in schizophrenia. Am J Psychiatry 165:1507-1509.

Febo M, Akbarian S, Schroeder FA, Ferris CF. (2009) Cocaine-induced metabolic activation in cortico-limbic circuitry is increased after exposure to the histone deacetylase inhibitor, sodium butyrate. Neurosci Lett. 465: 267-271.

Connor CM, Guo Y, Akbarian S (2009) Cingulate white matter neurons in bipolar disorder and schizophrenia. Biological Psychiatry 2009 Sep 1;66(5):486-93. Epub 2009 Jun 25.

Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z, Akbarian S (2010) Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc. Natl. Acad. Sci. USA (PNAS) (Early Edition online April 26th 2010).

Jakovcevski, M, Guo Y, Su Q, Gao G, Akbarian S (2010) rAAV9-a human-derived adeno-associated virus vector for efficient transgene expression in mouse cingulate cortex. Cold Spring Harbor Protocols 2010(4):pdb:prot5417.

Potential Rotation Projects

1. Drug-induced adaptations in neuronal circuitry contributing to psychosis or addiction could be viewed as a form of neuronal plasticity and thus may depend on similar molecular mechanisms that operate in learning and memory centers of the brain. The goal of this project is treat mice with chromatin modifying drugs and to explore the resulting molecular adaptations in nuclei of neurons located in fore- and hindbrain.  Students will gain experience in mouse genetics, neuroanatomy and various chromatin assays. Furthermore, students will have the opportunity to study current models of major psychiatric disease, including schizophrenia, mood disorders and addiction.

2. The genome of vertebrates is subject to epigenetic modifications, including the methylation of cytosine residues in symmetrically positioned CpG dinucleotides. DNA-methylation has profound effects on transcriptional activity and chromosomal stability. The goal of this project is to determine the regulation of DNA-methylation in developing and aging brain. Students will apply various techniques to examine DNA-methylation patterns of selected gene sequences in defined cell populations of the CNS.
   

Academic Background

Clinical Assistant in Psychiatry
Massachusetts General Hospital and McLean Hospital
Harvard Medical School
Belmont, MA

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

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