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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 a...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984042/
https://www.ncbi.nlm.nih.gov/pubmed/26900923
http://dx.doi.org/10.1038/nn.4256
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author 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
author_facet 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
author_sort Langfelder, Peter
collection PubMed
description 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.
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spelling pubmed-59840422018-06-01 Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice 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 Nat Neurosci Article 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. 2016-02-22 2016-04 /pmc/articles/PMC5984042/ /pubmed/26900923 http://dx.doi.org/10.1038/nn.4256 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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
Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title_full Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title_fullStr Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title_full_unstemmed Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title_short Integrated genomics and proteomics to define huntingtin CAG length-dependent networks in HD Mice
title_sort integrated genomics and proteomics to define huntingtin cag length-dependent networks in hd mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984042/
https://www.ncbi.nlm.nih.gov/pubmed/26900923
http://dx.doi.org/10.1038/nn.4256
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