PMID- 12881722 OWN - NLM STAT- MEDLINE DCOM- 20030925 LR - 20220129 IS - 1061-4036 (Print) IS - 1061-4036 (Linking) VI - 35 IP - 1 DP - 2003 Sep TI - Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. PG - 76-83 AB - 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. FAU - Zuccato, Chiara AU - Zuccato C AD - Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy. FAU - Tartari, Marzia AU - Tartari M FAU - Crotti, Andrea AU - Crotti A FAU - Goffredo, Donato AU - Goffredo D FAU - Valenza, Marta AU - Valenza M FAU - Conti, Luciano AU - Conti L FAU - Cataudella, Tiziana AU - Cataudella T FAU - Leavitt, Blair R AU - Leavitt BR FAU - Hayden, Michael R AU - Hayden MR FAU - Timmusk, Tonis AU - Timmusk T FAU - Rigamonti, Dorotea AU - Rigamonti D FAU - Cattaneo, Elena AU - Cattaneo E LA - eng GR - E.0840/TI_/Telethon/Italy PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20030727 PL - United States TA - Nat Genet JT - Nature genetics JID - 9216904 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (HTT protein, human) RN - 0 (Htt protein, mouse) RN - 0 (Htt protein, rat) 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 CIN - Nat Genet. 2003 Sep;35(1):13-4. PMID: 12947403 MH - Animals MH - Brain-Derived Neurotrophic Factor/*genetics MH - Cell Line MH - *Gene Expression Regulation MH - Humans MH - Huntingtin Protein MH - Huntington Disease/genetics MH - Mice MH - Mice, Knockout MH - Nerve Tissue Proteins/genetics/*physiology MH - Neurons/*physiology MH - Nuclear Proteins/genetics/*physiology MH - Promoter Regions, Genetic MH - Rats MH - Rats, Sprague-Dawley MH - Repressor Proteins/*genetics/physiology MH - Silencer Elements, Transcriptional MH - Transcription Factors/*genetics/physiology MH - Transcription, Genetic EDAT- 2003/07/26 05:00 MHDA- 2003/09/26 05:00 CRDT- 2003/07/26 05:00 PHST- 2003/02/11 00:00 [received] PHST- 2003/06/27 00:00 [accepted] PHST- 2003/07/26 05:00 [pubmed] PHST- 2003/09/26 05:00 [medline] PHST- 2003/07/26 05:00 [entrez] AID - ng1219 [pii] AID - 10.1038/ng1219 [doi] PST - ppublish SO - Nat Genet. 2003 Sep;35(1):76-83. doi: 10.1038/ng1219. Epub 2003 Jul 27.