Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes

@article{Zuccato2003HuntingtinIW,
  title={Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes},
  author={Chiara Zuccato and Marzia Tartari and Andrea Crotti and Donato Goffredo and Marta Valenza and Luciano Conti and Tiziana Cataudella and Blair R. Leavitt and Michael R. Hayden and T{\~o}nis Timmusk and Dorotea Rigamonti and Elena Cattaneo},
  journal={Nature Genetics},
  year={2003},
  volume={35},
  pages={76-83}
}
Huntingtin protein is mutated in Huntington disease. We previously reported that wild-type but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; ref. 2). Here we show that the neuron restrictive silencer element (NRSE) is the target of wild-type huntingtin activity on BDNF promoter II. Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic… Expand
Widespread Disruption of Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor Occupancy at Its Target Genes in Huntington's Disease
TLDR
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, and suggesting that relief of REST/NRSF mediated repression can restore aberrant neuronal gene transcription in HD. Expand
Sp1 Regulates Human Huntingtin Gene Expression
TLDR
This study cloned 1,795 bp of the 5′ flanking region of the human huntingtin gene and identified a 106-bp fragment containing the transcription start site as the minimal region necessary for promoter activity, revealing several putative regulatory elements including Sp1, NF-κB, HIF, CREB, NRSF, P53, YY1, AP1, and STAT in the huntingtin promoter. Expand
The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease
TLDR
The results show that direct knockdown of endogenous Hsp90 significantly reduces the levels of REST and mutant Huntingtin, decreased the percentage of cells with mHtt in nucleus and rescued cells frommHtt-induced cellular cytotoxicity, thereby providing neuroprotective activity. Expand
Transcriptional Activation of REST by Sp1 in Huntington's Disease Models
TLDR
The level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment, and evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription is provided. Expand
Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors
TLDR
A novel function for wild-type huntingtin as a co-factor of LXR is suggested, however, this activity is lost by mutant huntingtin that only interacts weakly with LXR. Expand
MeCP2: a novel Huntingtin interactor.
TLDR
It is reported that Htt directly interacts with methyl-CpG binding protein 2 (MeCP2) in mouse and cellular models of HD and these findings suggest that aberrant interactions between Htt and MeCP2 contribute to transcriptional dysregulation in HD. Expand
Loss of Huntingtin Function Complemented by Small Molecules Acting as Repressor Element 1/Neuron Restrictive Silencer Element Silencer Modulators*
TLDR
A cell-based reporter assay for monitoring RE1/NRSE silencing activity is developed and validated and suggests a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1-NRSE-regulated neuronal genes. Expand
Decreased association of the transcription factor Sp1 with genes downregulated in Huntington's disease
TLDR
It is found that mutant huntingtin dissociates Sp1 from target promoters, inhibiting transcription of specific genes in transgenic HD mouse brain, in striatal HD cells, and in human HD brain. Expand
Transcriptional regulation of the neuropeptide VGF by the neuron-restrictive silencer factor/neuron-restrictive silencer element
TLDR
It is shown that the NRSE sequence of the VGF gene critically regulates the repression of VGF expression in NMB cells through a mechanism that is dependent on VGF-NRSE. Expand
Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice
TLDR
It is indicated that NRSF, specifically REST4, may protect the developing brain from ethanol, and new evidence is provided thatNRSF can be a therapeutic target in foetal alcohol syndrome (FAS). Expand
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TLDR
Results support the idea that sequential proteolysis by caspase 3 and calpain may regulate huntingtin function at membranes and produce N-terminal mutant fragments that aggregate and cause cellular dysfunction in HD. Expand
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