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Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease
- Source :
- Human molecular genetics, vol 25, iss 16
- Publication Year :
- 2016
- Publisher :
- Oxford University Press, 2016.
-
Abstract
- Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene-encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component, however, has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing. Alternative splicing is a critical mechanism for expanding regulatory and functional diversity from a limited number of genes, and is particularly complex in the mammalian brain. Here we carried out a deep RNA-seq analysis of the BA4 (Brodmann area 4) motor cortex from seven human HD brains and seven controls to systematically discover aberrant alternative splicing events and characterize potential associated splicing factors in HD. We identified 593 differential alternative splicing events between HD and control brains. Using two expanded panels with a total of 108 BA4 tissues from patients and controls, we identified four splicing factors exhibiting significantly altered expression levels in HD patient brains. Moreover, follow-up molecular analyses of one splicing factor PTBP1 revealed its impact on disease-associated splicing patterns in HD. Collectively, our data provide genomic evidence for widespread splicing dysregulation in HD brains, and suggest the role of aberrant alternative splicing in the pathogenesis of HD.
- Subjects :
- 0301 basic medicine
Huntington's Disease
Male
Huntingtin
Neurodegenerative
Medical and Health Sciences
Heterogeneous-Nuclear Ribonucleoproteins
Transcriptome
Mice
2.1 Biological and endogenous factors
Aetiology
Genetics (clinical)
Genetics
Genetics & Heredity
Huntingtin Protein
Motor Cortex
High-Throughput Nucleotide Sequencing
General Medicine
PTBP1
Articles
Biological Sciences
Middle Aged
Huntington Disease
RNA splicing
Neurological
Female
Autopsy
Biotechnology
Polypyrimidine Tract-Binding Protein
Adult
Biology
03 medical and health sciences
Splicing factor
Rare Diseases
Animals
Humans
Genetic Predisposition to Disease
Molecular Biology
Aged
Alternative splicing
Human Genome
Neurosciences
Brain Disorders
Gene expression profiling
Alternative Splicing
030104 developmental biology
Gene Expression Regulation
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics, vol 25, iss 16
- Accession number :
- edsair.doi.dedup.....7f4d0414bf8ee3dfe9dcae07accdb667