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

Abstract

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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Figure 1: NRSE is the target of wild-type huntingtin activity on BDNF promoter region II.
Figure 2: Assembly of transcription factors onto the NRSE in the BDNF promoter is differently affected by wild-type or mutant huntingtin.
Figure 3: Western-blot analyses of nuclear and cytoplasmic localization of REST/NRSF.
Figure 4: Wild-type huntingtin and REST/NRSF interact in vitro and in vivo.
Figure 5: Wild-type and mutant huntingtin regulate the levels of mRNAs transcribed from other NRSE-controlled genes.

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Acknowledgements

We thank D. Anderson, G. Mandel, E. Battaglioli and L. Magrassi for discussion and comments on the paper; D. Rubinsztein for reading the final version of the manuscript and for raising the point of the dominant-negative mechanism; D. Anderson and G. Mandel for their gift of the REST/NRSF antibodies and REST/NRSF-Myc construct; A. Paquette and A. Ronchi for suggestions on the EMSA; R. Chiesa for the biotinylation protocol; and G. Simonutti for help and advice on the confocal analyses. This study was supported by the Huntington's Disease Society of America and Telethon and supported in part by the Hereditary Disease Foundation, Ministero dell'Istruzione dell'Università e della Ricerca Scientifica and Fondazione Cariplo (to E.C.); The Canadian Institutes of Health Research, Huntington's Disease Society of America and Hereditary Disease Foundation (to M.R.H.); and The Academy of Finland, Sigrid Juselius Foundation and Estonian Science Foundation (to T.T.). E.C. and M.R.H. are members of the Coalition for the Cure (Huntington's Disease Society of America) and of the Cure HD Initiative (Hereditary Disease Foundation). M.R.H. holds a Canada Research Chair in Human Genetics.

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Correspondence to Elena Cattaneo.

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Zuccato, C., Tartari, M., Crotti, A. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35, 76–83 (2003) doi:10.1038/ng1219

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