Erforschung transkriptioneller Dysregulation bei Morbus Huntington: Durch Genom-weite Kartierung von Genen, deren Promotoren direkt vom Protein Huntingtin beeinflusst werden, sollen Erkenntnisse über den Umfang und die Mechanismen von Transkriptionsstörun

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Huntington s disease (HD) is an inherited neurodegenerative disorder that causes cognitive decline and progressive motor impairment in affected individuals and eventually leads to death. HD is caused by an expansion of a GAG triplet repeat sequence in the gene IT 15, coding for a polyglutamine stretch in the protein huntingtin. The exact mechanism by which mutant huntingtin causes cellular dysfunction and cell death is unknown. Transcriptional deregulation has emerged as an important contributor to pathogenesis in HD. Huntingtin has been shown to interact with a number of transcription factors and analyses of gene expression patterns revealed alterations in messenger RNA levels of hundreds of genes in brain and peripheral tissues in HD. It is not known what proportion of the observed changes in messenger RNA levels results from direct effects of mutant huntingtin on gene promoters. In order to address this question, we will use recently developed ChlP-on-chip technology, combining chromatin immuno-precipitation (ChIP) and promoter microarray analysis. This approach allows for genome-wide in vivo mapping of gene promoters directly affected by huntingtin which in turn should help identify specific transcriptional pathways in vivo and provide new insights into the pathogenesis of HD. Moreover, comprehensive identification of gene targets of mutant huntingtin could greatly facilitate the search for biomarkers and specific therapies in HD.