Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq Analysis in Huntington's disease (HD) peripheral blood mononuclear cell samples

ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of the CAG nucleotide repeat in the first exon of the huntingtin (HTT) gene, with an onset between the second and third decades of life and slow progression. The pathogenesis of several of HD involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. To elucidate potential variations in gene expression in HD, a transcriptome study was conducted on 15 HD subjects and 15 controls, all of Sicilian origin, starting from peripheral blood mononuclear cell samples. A total of 7179 different statistically significant genes were identified between the two cohorts. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) terms were employed to explore the pathways influenced by differentially expressed mRNAs. GSEA revealed GO pathways strongly associated with HD, i.e. all GO biological process terms encompassing ribosome functions and structure are all highly negatively expressed phenotypes, with a large number of genes being dysregulated. This leads to the hypothesis that the processing chain leading to protein translation (via ribosomes) from mRNA is somehow impaired. In addition, genes and non-coding RNAs (ncRNAs) that play a regulatory role in various transcriptional processes were dysregulated. We can hypothesize that the whole process, from transcription to translation, is somehow compromised in HD subjects who have been genetically diagnosed with the expansion of the CAG triplet of the first exon of the HTT gene.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Giovanna Ventola

PROVIDER: E-MTAB-14696 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.

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RNA-seq Analysis in Huntington's disease (HD) peripheral blood mononuclear cell samples

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