Nature Genetics35, 76 - 83 (2003)
Published online: 27 July 2003; | doi:10.1038/ng1219
Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
Chiara Zuccato1, 4, Marzia Tartari1, 4, Andrea Crotti1, Donato Goffredo1, Marta Valenza1, Luciano Conti1, Tiziana Cataudella1, Blair R Leavitt2, Michael R Hayden2, Tõnis Timmusk3, Dorotea Rigamonti1
& Elena Cattaneo1
1
Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
2
Centre for Molecular Medicine and Therapeutics Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
3
Institute of Biotechnology, University of Helsinki, Helsinki, Finland and Department of Gene Technology, Tallinn Technical University and National Institute of Chemical Physics and Biophysics, Tallinn, Estonia.
Huntingtin protein is mutated in Huntington disease1. 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 NRSE3,
4. 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 phenotype5. 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.
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