Chromatin Pathology in Cerebral Cortex of Schizophrenics

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

DESCRIPTION (provided by applicant): Dysfunction of the prefrontal cortex (PFC) is thought to play a key role in the neurobiology of schizophrenia. In particular, the deficit syndrome which includes negative symptoms such as anhedonia, amotivation, apathy and poverty of thought content, is attributed to PFC malfunction. Dysregulated gene expression may contribute to impaired cellular function of prefrontal neurons and glia, but the underlying molecular pathology remains unclear. Chromatin remodeling at gene promoter regions is increasingly recognized as a key control point of gene expression and may, therefore, contribute to altered gene expression in PFC of schizophrenics. Presently, nothing is known about chromatin regulation in normal and in diseased human brain. Chromatin immunoprecipitation assays (ChIP), in combination with DNA microarrays for promoter and other 5'regulatory gene sequences (chip-on-ChlP), are a powerful tool to map chromatin function on a comprehensive, genome-wide scale. Recently, chip-on-ChIP was used to study transcriptional regulation in human liver and pancreas. However, it is not known if chromatin immunoprecipitation techniques and chip-on-ChlP are applicable to human postmortem brain. Here, we will use chip-on-ChIP in order to examine posttranslational histone modifications, a major form of chromatin remodeling important for epigenetic control of gene expression, in PFC of schizophrenics and matched controls. Our experiments will rely on custom-made promoter microarrays and on our modified chromatin immunoprecipitation assay specifically designed for postmortem brain. It is expected that this novel approach will (i) provide first insights into posttranslational chromatin imprints regulating gene expression in human brain and (ii) test the hypothesis that dysregulated gene expression in PFC of schizophrenics is associated with altered chromatin remodeling and epigenetic modifications of the promoter. Finally, the proposed studies will provide the framework for future proposals designed to map histone modification patterns across entire chromosomes in human brain, including alterations in major psychiatric disease.