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

@article{citeulike:264033, 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.}, address = {Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.}, author = {Zuccato, C. and Tartari, M. and Crotti, A. and Goffredo, D. and Valenza, M. and Conti, L. and Cataudella, T. and Leavitt, B. R. and Hayden, M. R. and Timmusk, T. and Rigamonti, D. and Cattaneo, E.}, citeulike-article-id = {264033}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/ng1219}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12881722}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12881722}, doi = {10.1038/ng1219}, issn = {1061-4036}, journal = {Nat Genet}, keywords = {03, bdnf, expression, gene\_, hd, nrse, nrsf, pathology, rest}, month = {September}, number = {1}, pages = {76--83}, posted-at = {2008-09-11 14:20:35}, priority = {2}, title = {Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.}, url = {http://dx.doi.org/10.1038/ng1219}, volume = {35}, year = {2003} }

TY - JOUR ID - citeulike:264033 L3 - citeulike-article-id:264033 N2 - 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. IS - 1 JF - Nat Genet SN - 1061-4036 AD - Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. EP - 83 TI - Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. VL - 35 SP - 76 KW - 03 KW - bdnf KW - expression KW - gene_ KW - hd KW - nrse KW - nrsf KW - pathology KW - rest AU - Zuccato, C AU - Tartari, M AU - Crotti, A AU - Goffredo, D AU - Valenza, M AU - Conti, L AU - Cataudella, T AU - Leavitt, BR AU - Hayden, MR AU - Timmusk, T AU - Rigamonti, D AU - Cattaneo, E PY - 2003/09// UR - http://dx.doi.org/10.1038/ng1219 ER -