Unbiased Profiling of Isogenic Huntington Disease hPSC-Derived CNS and Peripheral Cells Reveals Strong Cell-Type Specificity of CAG Length Effects

a broad range of CAG repeat lengths. We used genome editing to generate an allelic panel of isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying CAG repeat lengths in the first exon of HTT . Functional analyses in differentiated neural cells revealed CAG repeat length-related abnormalities in mitochondrial respiration and oxidative stress and enhanced susceptibility to DNA damage. To explore tissue-specific effects in HD, we differentiated the IsoHD panel into neural progenitor cells, neurons, hepatocytes, and muscle cells. Transcriptomic and proteomic analyses of the resultant cell types identi-fied CAG repeat length-dependent and cell-type-specific molecular phenotypes. We anticipate that the IsoHD panel and transcriptomic and proteomic data will serve as a versatile, open-access platform to dissect the molecular factors contributing to HD pathogenesis.

[1]  F. Ginhoux,et al.  Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells , 2017, Stem cell reports.

[2]  Yujin E. Kim,et al.  Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. , 2016, Molecular cell.

[3]  Daniel G. Miller,et al.  A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy‐Affected Skeletal Muscles , 2016, Stem Cells Translational Medicine.

[4]  S. Illarioshkin,et al.  Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons , 2016, Molecular Neurodegeneration.

[5]  B. Gao,et al.  Hepatocytes: a key cell type for innate immunity , 2015, Cellular and Molecular Immunology.

[6]  L. Leinwand,et al.  Developmental myosins: expression patterns and functional significance , 2015, Skeletal Muscle.

[7]  A. Kurtz,et al.  Human Embryonic and Induced Pluripotent Stem Cell Research Trends: Complementation and Diversification of the Field , 2015, Stem cell reports.

[8]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[9]  J. Marcinkowski,et al.  Skeletal muscle pathology in Huntington's disease , 2014, Front. Physiol..

[10]  David C Hay,et al.  Deriving functional hepatocytes from pluripotent stem cells. , 2014, Current protocols in stem cell biology.

[11]  C. Kyriacou,et al.  Glutathione peroxidase activity is neuroprotective in models of Huntington's disease , 2013, Nature Genetics.

[12]  Dong Ryul Lee,et al.  Neuronal Properties, In Vivo Effects, and Pathology of a Huntington's Disease Patient‐Derived Induced Pluripotent Stem Cells , 2012, Stem cells.

[13]  T. Gillis,et al.  Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. , 2012, Cell stem cell.

[14]  L. Scorrano,et al.  Shaping the role of mitochondria in the pathogenesis of Huntington's disease , 2012, The EMBO journal.

[15]  T. Gillis,et al.  Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver , 2011, PloS one.

[16]  Hyoung-Gon Lee,et al.  Pathological implications of cell cycle re-entry in Alzheimer disease , 2010, Expert Reviews in Molecular Medicine.

[17]  D. Ehrnhoefer,et al.  Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. , 2010, Human molecular genetics.

[18]  P. Lansdorp,et al.  Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells. , 2009, Experimental cell research.

[19]  M. Hayden,et al.  A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease , 2008, The Journal of experimental medicine.

[20]  Oksana Gavrilova,et al.  p53 Regulates Mitochondrial Respiration , 2006, Science.

[21]  M. MacDonald,et al.  HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. , 2005, Human molecular genetics.

[22]  S. Lees-Miller,et al.  Doxorubicin Activates ATM-dependent Phosphorylation of Multiple Downstream Targets in Part through the Generation of Reactive Oxygen Species* , 2004, Journal of Biological Chemistry.

[23]  Jane S. Paulsen,et al.  A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length , 2004, Clinical genetics.

[24]  Elizabeth Evans,et al.  Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. , 2003, Human molecular genetics.

[25]  S. Ackerman,et al.  Oxidative stress, cell cycle, and neurodegeneration. , 2003, The Journal of clinical investigation.

[26]  J. Nevins,et al.  Huntingtin Is Present in the Nucleus, Interacts with the Transcriptional Corepressor C-terminal Binding Protein, and Represses Transcription* , 2002, The Journal of Biological Chemistry.

[27]  R. Myers,et al.  Juvenile onset Huntington's disease--clinical and research perspectives. , 2001, Mental retardation and developmental disabilities research reviews.

[28]  S. W. Davies,et al.  Formation of polyglutamine inclusions in non-CNS tissue. , 1999, Human molecular genetics.

[29]  James F. Gusella,et al.  Differential Expression of Normal and Mutant Huntington's Disease Gene Alleles , 1996, Neurobiology of Disease.

[30]  Joseph B. Martin.  Huntington's disease , 1984, Neurology.

[31]  J. Botas,et al.  Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice. , 2018 .

[32]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[33]  Jacqueline K. White,et al.  Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. , 1999, Human molecular genetics.