ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease.

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Research Abstract Details 

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ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Abstract Text:

Hoon Ryu,Junghee Lee,Sean W Hagerty,Byoung Yul Soh,Sara E McAlpin,Kerry A Cormier,Karen M Smith,Robert J Ferrante,

Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients.

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Publishing Authors By Initials

H Ryu,J Lee,SW Hagerty,BY Soh,SE McAlpin,KA Cormier,KM Smith,RJ Ferrante,

For similar genetic processes: gene expression regulation: up-regulation research abstracts see: genetic processes: gene expression regulation: up-regulation research

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ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 103

Page Numbers: 19176-81

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 1

MONTH: 12

YEAR: 2006

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: metabolism

Chemical & Substance for Abstract: ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Information

Substance Name: SETDB1 protein, mouse

Registry Number: EC 2.1.1.-

Grant and Affiliation Information for ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease.

AFFILIATION: Geriatric Research Education and Clinical Center, Bedford Veteran's Affairs Medical Center, Bedford, MA 01730, USA. hoonryu@bu.edu

Country: United States

AGENCY: United States NIA

GRANT: P30 AG 13846

ACRONYM: AG

MEDLINETA: Proc Natl Acad Sci U S A

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