PMID- 17596446
OWN - NLM
STAT- MEDLINE
DCOM- 20070801
LR  - 20220129
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 27
IP  - 26
DP  - 2007 Jun 27
TI  - Widespread disruption of repressor element-1 silencing transcription 
      factor/neuron-restrictive silencer factor occupancy at its target genes in 
      Huntington's disease.
PG  - 6972-83
AB  - Huntingtin is a protein that is mutated in Huntington's disease (HD), a dominant 
      inherited neurodegenerative disorder. We previously proposed that, in addition to 
      the gained toxic activity of the mutant protein, selective molecular dysfunctions 
      in HD may represent the consequences of the loss of wild-type protein activity. 
      We first reported that wild-type huntingtin positively affects the transcription 
      of the brain-derived neurotrophic factor (BDNF) gene, a cortically derived 
      survival factor for the striatal neurons that are mainly affected in the disease. 
      Mutation in huntingtin decreases BDNF gene transcription. One mechanism involves 
      the activation of repressor element 1/neuron-restrictive silencer element 
      (RE1/NRSE) located within the BDNF promoter. We now show that increased binding 
      of the RE1 silencing transcription factor/neuron-restrictive silencer factor 
      (REST/NRSF) repressor occurs at multiple genomic RE1/NRSE loci in HD cells, in 
      animal models, and in postmortem brains, resulting in a decrease of 
      RE1/NRSE-mediated gene transcription. The same molecular phenotype is produced in 
      cells and brain tissue depleted of endogenous huntingtin, thereby directly 
      validating the loss-of-function hypothesis of HD. Through a ChIP (chromatin 
      immunoprecipitation)-on-chip approach, we examined occupancy of multiple 
      REST/NRSF target genes in the postmortem HD brain, providing the first example of 
      the application of this technology to neurodegenerative diseases. Finally, we 
      show that attenuation of REST/NRSF binding restores BDNF levels, suggesting that 
      relief of REST/NRSF mediated repression can restore aberrant neuronal gene 
      transcription in HD.
FAU - Zuccato, Chiara
AU  - Zuccato C
AD  - Department of Pharmacological Sciences and Centre for Stem Cell Research, 
      University of Milan, Via Balzaretti 9, 20133 Milano, Italy.
FAU - Belyaev, Nikolai
AU  - Belyaev N
FAU - Conforti, Paola
AU  - Conforti P
FAU - Ooi, Lezanne
AU  - Ooi L
FAU - Tartari, Marzia
AU  - Tartari M
FAU - Papadimou, Evangelia
AU  - Papadimou E
FAU - MacDonald, Marcy
AU  - MacDonald M
FAU - Fossale, Elisa
AU  - Fossale E
FAU - Zeitlin, Scott
AU  - Zeitlin S
FAU - Buckley, Noel
AU  - Buckley N
FAU - Cattaneo, Elena
AU  - Cattaneo E
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - P50 NS016367/NS/NINDS NIH HHS/United States
GR  - NS16367/NS/NINDS NIH HHS/United States
GR  - R01 NS032765/NS/NINDS NIH HHS/United States
GR  - NS32765/NS/NINDS NIH HHS/United States
GR  - GGP06250/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Htt protein, mouse)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Brain Chemistry/*genetics
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Line, Transformed
MH  - Corpus Striatum/metabolism/pathology/physiopathology
MH  - Down-Regulation/genetics
MH  - Gene Expression Regulation/*genetics
MH  - Genetic Predisposition to Disease/*genetics
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*genetics
MH  - Immunoprecipitation/methods
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Nerve Tissue Proteins/genetics
MH  - Neurons/metabolism/pathology
MH  - Nuclear Proteins/genetics
MH  - Protein Binding/genetics
MH  - Repressor Proteins/*genetics/metabolism
MH  - Transcription Factors/*genetics/metabolism
PMC - PMC6672230
EDAT- 2007/06/29 09:00
MHDA- 2007/08/02 09:00
PMCR- 2007/12/27
CRDT- 2007/06/29 09:00
PHST- 2007/06/29 09:00 [pubmed]
PHST- 2007/08/02 09:00 [medline]
PHST- 2007/06/29 09:00 [entrez]
PHST- 2007/12/27 00:00 [pmc-release]
AID - 27/26/6972 [pii]
AID - 3230640 [pii]
AID - 10.1523/JNEUROSCI.4278-06.2007 [doi]
PST - ppublish
SO  - J Neurosci. 2007 Jun 27;27(26):6972-83. doi: 10.1523/JNEUROSCI.4278-06.2007.