title: Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.
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 found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Langfelder
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Cantle
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Doxa
authors.initials: D
authors.lastname: Chatzopoulou
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Lu
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Eliana Marisa
authors.initials: EM
authors.lastname: Ramos
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: El-Zein
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Yining
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Deverasetty
authors.affiliation: Evotec Munich GmbH, Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tebbe
authors.affiliation: Evotec Munich GmbH, Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaab
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lavery
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Aaronson
authors.affiliation: CHDI Foundation/CHDI Management Inc., Princeton, New Jersey, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Rosinski
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.|Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Giovanni
authors.identifier: http://orcid.org/0000-0003-2105-1061
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|Department of Biostatistics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, California, USA.|UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000502:physiology; D003342:Corpus Striatum / Q000473:pathology / Q000502:physiology; D005260:Female; D055879:Gene Knock-In Techniques / Q000379:methods; D053263:Gene Regulatory Networks / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D000071058:Huntingtin Protein; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D040901:Proteomics / Q000379:methods*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins