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Transcriptome and cistrome analysis in patients with spinocerebellar ataxia 17

Introduction: Mutant proteins which cause neurodegenerative diseases, such as TATA-box binding protein (TBP), interfere with basal and activated transcriptional machinery suggesting that alterations in gene transcription may be detectable in many tissues. Moreover, since mutant TBP is expressed in all tissues, including peripheral blood, we hypothesized that promoter recruitment and gene expression patterns in blood could in part reflect pathological processes observed in the brain. Results: In order to identify differential promoter recruitment in patients with spinocerebellar ataxia 17 (SCA-17), we isolated peripheral blood mononuclear cells and performed chromatin immunoprecipitation on chip using Affymetrix Human Promoter 1.0R and Agilent Human Promoter 244K microarrays. The results of the analysis showed increased promoter recruitment by the mutant TBP on both platforms, and included genes belonging to functional groups such as energy metabolism, transcription, signaling and ubiquitin/proteasome. In order to ascertain whether increased promoter binding by mutant TBP lead to changes in transcriptional activity, we also isolated RNA from peripheral blood of SCA-17 patients and performed microarray analysis using Affymetrix Human Genome U133 2.0 PLUS genechips. Expression profiling showed that majority of the differentially expressed genes were significantly down-regulated, indicating possible transcriptional disruption by the mutant protein. Conclusions: In conclusion, mutant proteins, such as TBP, interfere with normal transcriptional activity in peripheral blood cells and observed alterations may reflect pathological mechanisms involved in neurodegenerative diseases.

expression profiling; chip-on-chip; neurodegeneration; spinocerebellar ataxia 17

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