Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes - PubMed (original) (raw)
doi: 10.1038/ng1219. Epub 2003 Jul 27.
Marzia Tartari, Andrea Crotti, Donato Goffredo, Marta Valenza, Luciano Conti, Tiziana Cataudella, Blair R Leavitt, Michael R Hayden, Tõnis Timmusk, Dorotea Rigamonti, Elena Cattaneo
Affiliations
- PMID: 12881722
- DOI: 10.1038/ng1219
Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
Chiara Zuccato et al. Nat Genet. 2003 Sep.
Abstract
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 sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. We also report that wild-type huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. We conclude that wild-type huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identify a new mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes.
Comment in
- An expanded role for wild-type huntingtin in neuronal transcription.
Thompson LM. Thompson LM. Nat Genet. 2003 Sep;35(1):13-4. doi: 10.1038/ng0903-13. Nat Genet. 2003. PMID: 12947403 No abstract available.
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