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 a...

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Autores principales:	Matthew Hogel, Robert B Laprairie, Eileen M Denovan-Wright
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6cf98b69a20d48f2b48389cff0841946
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spelling	oai:doaj.org-article:6cf98b69a20d48f2b48389cff08419462021-11-18T07:11:59ZPromoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression.1932-620310.1371/journal.pone.0041152https://doaj.org/article/6cf98b69a20d48f2b48389cff08419462012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22815947/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Huntington'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.Matthew HogelRobert B LaprairieEileen M Denovan-WrightPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41152 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew Hogel Robert B Laprairie Eileen M Denovan-Wright Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression.
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	article
author	Matthew Hogel Robert B Laprairie Eileen M Denovan-Wright
author_facet	Matthew Hogel Robert B Laprairie Eileen M Denovan-Wright
author_sort	Matthew Hogel
title	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_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_sort	promoters are differentially sensitive to n-terminal mutant huntingtin-mediated transcriptional repression.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/6cf98b69a20d48f2b48389cff0841946
work_keys_str_mv	AT matthewhogel promotersaredifferentiallysensitivetonterminalmutanthuntingtinmediatedtranscriptionalrepression AT robertblaprairie promotersaredifferentiallysensitivetonterminalmutanthuntingtinmediatedtranscriptionalrepression AT eileenmdenovanwright promotersaredifferentiallysensitivetonterminalmutanthuntingtinmediatedtranscriptionalrepression
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Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression.

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