Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

Alice S. Chen-Plotkin; Ghazaleh Sadri-Vakili; George J. Yohrling; Melissa W. Braveman; Caroline L. Benn; Kelly E. Glajch; Derek P. DiRocco; Laurie A. Farrell; Dimitri Krainc; Silvia Gines; Marcy E. MacDonald; Jang Ho J Cha

doi:10.1016/j.nbd.2005.11.001

Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

Alice S. Chen-Plotkin, Ghazaleh Sadri-Vakili, George J. Yohrling, Melissa W. Braveman, Caroline L. Benn, Kelly E. Glajch, Derek P. DiRocco, Laurie A. Farrell, Dimitri Krainc, Silvia Gines, Marcy E. MacDonald, Jang Ho J Cha

Neurology

Research output: Contribution to journal › Article › peer-review

90 Scopus citations

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine tract within the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis; recent evidence suggests a defect in Sp1-mediated transcription. We used chromatin immunoprecipitation (ChIP) assays followed by real-time PCR to quantify the association of Sp1 with individual genes. We find that, despite normal protein levels and normal to increased overall nuclear binding activity, Sp1 has decreased binding to specific promoters of susceptible genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Genes whose mRNA levels are decreased in HD have abnormal Sp1-DNA binding, whereas genes with unchanged mRNA levels have normal levels of Sp1 association. Moreover, the altered binding seen with Sp1 is not found with another transcription factor, NF-Y. These findings suggest that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes.

Original language	English (US)
Pages (from-to)	233-241
Number of pages	9
Journal	Neurobiology of Disease
Volume	22
Issue number	2
DOIs	https://doi.org/10.1016/j.nbd.2005.11.001
State	Published - May 2006

Funding

We would like to thank the Massachusetts General Hospital Alzheimer Disease Research Center for supplying human postmortem brain samples. Supported by NINDS NS38106 (J.-H.J.C.), NS045242 (J.-H.J.C. and D.K.; PI: Hersch), NS32765 (M.E.M.), NS16367 (Huntington's Disease Center Without Walls, M.E.M), Glendorn Foundation (J.-H.J.C.), Hereditary Disease Foundation (G.S.-V.), and the HDSA Coalition for the Cure (J.-H.J.C. and M.E.M.). A.S.C.-P. was a Howard Hughes Medical Institute Medical Student Research Fellow.

Keywords

Chromatin immunoprecipitation
Gene regulation
Huntington's disease
Polyglutamine
Transcription
Transcription factor

ASJC Scopus subject areas

Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nbd.2005.11.001

Cite this

Chen-Plotkin, A. S., Sadri-Vakili, G., Yohrling, G. J., Braveman, M. W., Benn, C. L., Glajch, K. E., DiRocco, D. P., Farrell, L. A., Krainc, D., Gines, S., MacDonald, M. E., & Cha, J. H. J. (2006). Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease. Neurobiology of Disease, 22(2), 233-241. https://doi.org/10.1016/j.nbd.2005.11.001

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title = "Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease",

abstract = "Huntington's disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine tract within the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis; recent evidence suggests a defect in Sp1-mediated transcription. We used chromatin immunoprecipitation (ChIP) assays followed by real-time PCR to quantify the association of Sp1 with individual genes. We find that, despite normal protein levels and normal to increased overall nuclear binding activity, Sp1 has decreased binding to specific promoters of susceptible genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Genes whose mRNA levels are decreased in HD have abnormal Sp1-DNA binding, whereas genes with unchanged mRNA levels have normal levels of Sp1 association. Moreover, the altered binding seen with Sp1 is not found with another transcription factor, NF-Y. These findings suggest that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes.",

keywords = "Chromatin immunoprecipitation, Gene regulation, Huntington's disease, Polyglutamine, Transcription, Transcription factor",

author = "Chen-Plotkin, \{Alice S.\} and Ghazaleh Sadri-Vakili and Yohrling, \{George J.\} and Braveman, \{Melissa W.\} and Benn, \{Caroline L.\} and Glajch, \{Kelly E.\} and DiRocco, \{Derek P.\} and Farrell, \{Laurie A.\} and Dimitri Krainc and Silvia Gines and MacDonald, \{Marcy E.\} and Cha, \{Jang Ho J\}",

note = "Funding Information: We would like to thank the Massachusetts General Hospital Alzheimer Disease Research Center for supplying human postmortem brain samples. Supported by NINDS NS38106 (J.-H.J.C.), NS045242 (J.-H.J.C. and D.K.; PI: Hersch), NS32765 (M.E.M.), NS16367 (Huntington's Disease Center Without Walls, M.E.M), Glendorn Foundation (J.-H.J.C.), Hereditary Disease Foundation (G.S.-V.), and the HDSA Coalition for the Cure (J.-H.J.C. and M.E.M.). A.S.C.-P. was a Howard Hughes Medical Institute Medical Student Research Fellow.",

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AU - Chen-Plotkin, Alice S.

AU - Sadri-Vakili, Ghazaleh

AU - Yohrling, George J.

AU - Braveman, Melissa W.

AU - Benn, Caroline L.

AU - Glajch, Kelly E.

AU - DiRocco, Derek P.

AU - Farrell, Laurie A.

AU - Krainc, Dimitri

AU - Gines, Silvia

AU - MacDonald, Marcy E.

AU - Cha, Jang Ho J

N1 - Funding Information: We would like to thank the Massachusetts General Hospital Alzheimer Disease Research Center for supplying human postmortem brain samples. Supported by NINDS NS38106 (J.-H.J.C.), NS045242 (J.-H.J.C. and D.K.; PI: Hersch), NS32765 (M.E.M.), NS16367 (Huntington's Disease Center Without Walls, M.E.M), Glendorn Foundation (J.-H.J.C.), Hereditary Disease Foundation (G.S.-V.), and the HDSA Coalition for the Cure (J.-H.J.C. and M.E.M.). A.S.C.-P. was a Howard Hughes Medical Institute Medical Student Research Fellow.

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N2 - Huntington's disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine tract within the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis; recent evidence suggests a defect in Sp1-mediated transcription. We used chromatin immunoprecipitation (ChIP) assays followed by real-time PCR to quantify the association of Sp1 with individual genes. We find that, despite normal protein levels and normal to increased overall nuclear binding activity, Sp1 has decreased binding to specific promoters of susceptible genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Genes whose mRNA levels are decreased in HD have abnormal Sp1-DNA binding, whereas genes with unchanged mRNA levels have normal levels of Sp1 association. Moreover, the altered binding seen with Sp1 is not found with another transcription factor, NF-Y. These findings suggest that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes.

AB - Huntington's disease (HD) is a neurodegenerative disease caused by expansion of a polyglutamine tract within the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis; recent evidence suggests a defect in Sp1-mediated transcription. We used chromatin immunoprecipitation (ChIP) assays followed by real-time PCR to quantify the association of Sp1 with individual genes. We find that, despite normal protein levels and normal to increased overall nuclear binding activity, Sp1 has decreased binding to specific promoters of susceptible genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Genes whose mRNA levels are decreased in HD have abnormal Sp1-DNA binding, whereas genes with unchanged mRNA levels have normal levels of Sp1 association. Moreover, the altered binding seen with Sp1 is not found with another transcription factor, NF-Y. These findings suggest that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes.

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KW - Gene regulation

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KW - Transcription

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Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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