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Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression
Huntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which accumu...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399790/ https://www.ncbi.nlm.nih.gov/pubmed/22815947 http://dx.doi.org/10.1371/journal.pone.0041152 |
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author | Hogel, Matthew Laprairie, Robert B. Denovan-Wright, Eileen M. |
author_facet | Hogel, Matthew Laprairie, Robert B. Denovan-Wright, Eileen M. |
author_sort | Hogel, Matthew |
collection | PubMed |
description | Huntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients, animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression. An understanding of the effects of mHtt may lead to strategies to slow the progression of HD. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of the current models using two N-mHtt-affected promoters in two cell models of HD using overexpression of known N-mHtt-interacting transcription factors, promoter deletion and mutation analyses and in vitro promoter binding assays. Consequently, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at promoters. In this model, N-mHtt interacts with multiple partners whose presence and affinity for N-mHtt influence the severity of gene dysregulation. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as why some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N-mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt. |
format | Online Article Text |
id | pubmed-3399790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33997902012-07-19 Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression Hogel, Matthew Laprairie, Robert B. Denovan-Wright, Eileen M. PLoS One Research Article Huntington’s disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients, animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression. An understanding of the effects of mHtt may lead to strategies to slow the progression of HD. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of the current models using two N-mHtt-affected promoters in two cell models of HD using overexpression of known N-mHtt-interacting transcription factors, promoter deletion and mutation analyses and in vitro promoter binding assays. Consequently, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at promoters. In this model, N-mHtt interacts with multiple partners whose presence and affinity for N-mHtt influence the severity of gene dysregulation. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as why some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N-mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt. Public Library of Science 2012-07-18 /pmc/articles/PMC3399790/ /pubmed/22815947 http://dx.doi.org/10.1371/journal.pone.0041152 Text en Hogel et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hogel, Matthew Laprairie, Robert B. Denovan-Wright, Eileen M. Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title | Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title_full | Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title_fullStr | Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title_full_unstemmed | Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title_short | Promoters Are Differentially Sensitive to N-Terminal Mutant Huntingtin-Mediated Transcriptional Repression |
title_sort | promoters are differentially sensitive to n-terminal mutant huntingtin-mediated transcriptional repression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399790/ https://www.ncbi.nlm.nih.gov/pubmed/22815947 http://dx.doi.org/10.1371/journal.pone.0041152 |
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