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


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.


  1. 1

    Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosome. Cell 72, 971–983 (1993).

  2. 2

    Zuccato, C. et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293, 493–498 (2001).

  3. 3

    Chong, J.A. et al. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80, 949–957 (1995).

  4. 4

    Schoenherr, C.J. & Anderson, D.J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360–1363 (1995).

  5. 5

    Schoenherr, C.J., Paquette, A.J. & Anderson, D.J. Identification of potential target genes for the neuron-restrictive silencer factor. Proc. Natl. Acad. Sci. USA 93, 9881–9886 (1996).

  6. 6

    Rubinsztein, D.C. Lessons from animal models of Huntington's disease. Trends Genet. 18, 202–209 (2002).

  7. 7

    Cattaneo, E. et al. Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci. 24, 182–188 (2001).

  8. 8

    Timmusk, T. et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10, 475–489 (1993).

  9. 9

    Timmusk, T. at al. Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice. J. Cell Biol. 128, 185–199 (1995).

  10. 10

    Ehrlich, M.E. et al. ST14A cells have properties of a medium-spiny neuron. Exp. Neurol. 167, 215–226 (2001).

  11. 11

    Rigamonti, D. et al. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20, 3705–3713 (2000).

  12. 12

    Trettel, F. et al. Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum. Mol. Genet. 9, 2799–2809 (2000).

  13. 13

    Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

  14. 14

    Timmusk, T., Palm, K., Lendahl, U. & Metsis, M. brain-derived neurotrophic Factor expression in vivo is under the control of neuron-restrictive silencer element. J. Biol. Chem. 274, 1078–1084 (1999).

  15. 15

    Huang, Y., Myers, S.J. & Dingledine, R. Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat. Neurosci. 2, 867–872 (1999).

  16. 16

    Ballas, N. et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron 31, 353–365 (2001).

  17. 17

    Palm, K., Belluardo, N., Metsis, M. & Timmusk, T. Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J. Neurosci. 18, 1280–1296 (1998).

  18. 18

    Palm, K., Metsis, M. & Timmusk, T. Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. Brain Res. Mol. Brain Res. 72, 30–39 (1999).

  19. 19

    Koenigsberger, C., Chicca, J.J. 2nd, Amoureux, M.C., Edelman, G.M. & Jones, F.S. Differential regulation by multiple promoters of the gene encoding the neuron-restrictive silencer factor. Proc. Natl. Acad. Sci. USA 97, 2291–2296 (2000).

  20. 20

    Lee, J.H., Shimojo, M., Chai, Y.G. & Hersh, L.B. Studies on the interaction of REST4 with the cholinergic repressor element-1/neuron restrictive silencer element. Brain Res. Mol. Brain Res. 80, 88–98 (2000).

  21. 21

    Shimojo, M., Lee, J.H. & Hersh, L.B. Role of zinc finger domains of the transcription factor neuron-restrictive silencer factor/repressor element-1 silencing transcription factor in DNA binding and nuclear localization. J. Biol. Chem. 276, 13121–13126 (2001).

  22. 22

    Hodgson, J.G. et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23, 181–192 (1999).

  23. 23

    Dyer, R.B. & McMurray, C.T. Mutant protein in Huntington's disease is resistant to proteolysis in affected brain. Nat. Genet. 29, 270–278 (2001).

  24. 24

    Wellington, C.L. et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158–9167 (1998).

  25. 25

    Kim, Y.J. et al. Caspase 3 cleavage N-terminal fragment of wild-type or mutant huntingtin are presented in normal and Huntington's disease brain associate with membrains and undergo calpain dependent proteolysis. Proc. Natl. Acad. Sci. USA 98, 12784–12789 (2001).

  26. 26

    Gafni, J & Ellerby, L.M. Calpain activation in Huntington's disease. J. Neurosci. 22, 4842–4849 (2002).

  27. 27

    Zhang, Y et al. Depletion of wild-type Huntingtin in mouse models of neurologic diseases. J. Neurochem. (in the press).

  28. 28

    Steffan, J.S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001).

  29. 29

    Goffredo, D. et al. Calcium-dependent cleavage of endogenous wild-type Huntingtin in primary cortical neurons. J. Biol. Chem. 277, 39594–39598 (2002).

  30. 30

    Gorski, K., Carneiro, M. & Schibler, U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell 47, 767–776 (1986).

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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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