title: Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease.
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.
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Juw Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: The Raymond G Perelman Center for Cellular and Molecular Therapy, The Children's Hospital of Philadelphia, PA, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Yida
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Tseng
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Shihao
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Anatomy and Medical Imaging and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Waldvogel
authors.affiliation: Department of Anatomy and Medical Imaging and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Department of Anatomy and Medical Imaging and Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Division of Neurobiology; Departments of Psychiatry, Neurology Neuroscience, and Pharmacology; and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: The Raymond G Perelman Center for Cellular and Molecular Therapy, The Children's Hospital of Philadelphia, PA, USA yxing@ucla.edu davidsonbl@email.chop.edu.|The Department of Pathology & Laboratory Medicine, The University of Pennsylvania, PA 19104, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.affiliation: Department of Microbiology, Immunology, & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA yxing@ucla.edu davidsonbl@email.chop.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001344:Autopsy; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000096:biosynthesis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism* / Q000473:pathology; D038941:Polypyrimidine Tract-Binding Protein / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D000071058:Huntingtin Protein; C450006:PTBP1 protein, human; D038941:Polypyrimidine Tract-Binding Protein