Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice

To gain insight into how mutant huntingtin ( mHtt ) CAG repeat length modifies Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We find repeat length dependent transcriptional signatures...

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Published inNature neuroscience Vol. 19; no. 4; pp. 623 - 633
Main Authors Langfelder, Peter, Cantle, Jeffrey P., Chatzopoulou, Doxa, Wang, Nan, Gao, Fuying, Al-Ramahi, Ismael, Lu, Xiao-Hong, Ramos, Eliana Marisa, El-Zein, Karla, Zhao, Yining, Deverasetty, Sandeep, Tebbe, Andreas, Schaab, Christoph, Lavery, Daniel J., Howland, David, Kwak, Seung, Botas, Juan, Aaronson, Jeffrey S., Rosinski, Jim, Coppola, Giovanni, Horvath, Steve, Yang, X. William
Format Journal Article
LanguageEnglish
Published 22.02.2016
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Abstract To gain insight into how mutant huntingtin ( mHtt ) CAG repeat length modifies Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHtt CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo .
AbstractList To gain insight into how mutant huntingtin ( mHtt ) CAG repeat length modifies Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHtt CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo .
Author Schaab, Christoph
Wang, Nan
Gao, Fuying
Lu, Xiao-Hong
Zhao, Yining
Cantle, Jeffrey P.
Ramos, Eliana Marisa
Rosinski, Jim
Horvath, Steve
Al-Ramahi, Ismael
Kwak, Seung
Howland, David
Botas, Juan
El-Zein, Karla
Aaronson, Jeffrey S.
Langfelder, Peter
Yang, X. William
Coppola, Giovanni
Chatzopoulou, Doxa
Lavery, Daniel J.
Deverasetty, Sandeep
Tebbe, Andreas
AuthorAffiliation 4 UCLA Brain Research Institute, Los Angeles, CA 90095, USA
9 CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA
2 Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
3 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
10 Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
8 Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
6 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
1 Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
7 Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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  organization: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA UCLA Brain Research Institute, Los Angeles, CA 90095, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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  organization: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA UCLA Brain Research Institute, Los Angeles, CA 90095, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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  surname: Coppola
  fullname: Coppola, Giovanni
  organization: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA UCLA Brain Research Institute, Los Angeles, CA 90095, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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  organization: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA UCLA Brain Research Institute, Los Angeles, CA 90095, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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  givenname: X. William
  surname: Yang
  fullname: Yang, X. William
  organization: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA UCLA Brain Research Institute, Los Angeles, CA 90095, USA Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Evotec (Munchen) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany CHDI Foundation/CHDI Management Inc., Princeton NJ 08540, USA Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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Snippet To gain insight into how mutant huntingtin ( mHtt ) CAG repeat length modifies Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and...
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Title Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
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