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Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes

Abstract

Many genes whose expression is restricted to neurons in the brain contain a silencer element (RE1/NRSE) that limits transcription in nonneuronal cells by binding the transcription factor REST (also named NRSF or XBR). Although two independent domains of REST are known to confer repression, the mechanisms of transcriptional repression by REST remain obscure. We provide multiple lines of evidence that the N-terminal domain of REST represses transcription of the GluR2 and type II sodium-channel genes by recruiting the corepressor Sin3A and histone deacetylase (HDAC) to the promoter region in nonneuronal cells. These results identify a general mechanism for controlling the neuronal expression pattern of a specific set of genes via the RE1 silencer element.

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Figure 1: Trichostatin A derepresses the GluR2 gene by a silencer-dependent mechanism.
Figure 2: Deletion scan of the proximal GluR2 promoter identifies two TSA-sensitive regions.
Figure 3: Selectivity of trichostatin A effect.
Figure 4: The N-terminal repressor domain of REST is TSA-sensitive.
Figure 5: Co-immunoprecipitation of REST, Sin3A and HDAC1.
Figure 6: TSA increased the association of acetylated histone H3 and H4 with GluR2 promoter in C6 glioma but not cortical neurons.

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References

  1. Kraner, S. D., Chong, J. A., Tsay, H. J. & Mandel, G. Silencing the type II sodium channel gene: a model for neural-specific gene regulation. Neuron 9, 37– 44 (1992).

    Article  CAS  Google Scholar 

  2. Mori, N., Schoenherr, C., Vandenbergh, D. J. & Anderson, D. J. A common silencer element in the SCG10 and type II Na+ channel genes binds a factor present in nonneuronal cells but not in neuronal cells. Neuron 9, 45–54 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  6. Myers, S. J. et al. Transcriptional regulation of the GluR2 gene: Neural-specific expression, multiple promoters, and regulatory elements. J. Neurosci. 18, 6723–6739 ( 1998).

    Article  CAS  Google Scholar 

  7. Chen, Z. F., Paquette, A. J. & Anderson, D. J. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat. Genet. 20, 136–42 (1998).

    Article  CAS  Google Scholar 

  8. 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).

    CAS  PubMed  Google Scholar 

  9. Kallunki, P., Edelman, G. M. & Jones, F. S. The neural restrictive silencer element can act as both a repressor and enhancer of L1 cell adhesion molecule gene expression during postnatal development. Proc. Natl. Acad. Sci. USA 95, 3233–3238 (1998).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Alland, L. et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387, 49– 55 (1997).

    Article  CAS  Google Scholar 

  12. Hassig, C. A., Fleischer, T. C., Billin, A. N., Schreiber, S. L. & Ayer, D. E. Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89, 341–347 ( 1997).

    Article  CAS  Google Scholar 

  13. Laherty, C. D. et al. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89, 349–356 (1997).

    Article  CAS  Google Scholar 

  14. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  Google Scholar 

  15. Luo, R. X., Postigo, A. A. & Dean, D. C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463– 473 (1998).

    Article  CAS  Google Scholar 

  16. Nomura, T. et al. Ski is a component of the histone deacetylase complex required for transcriptional repression by mad and thyroid hormone receptor. Genes Dev. 13, 412–423 ( 1999).

    Article  CAS  Google Scholar 

  17. Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 ( 1998).

    Article  CAS  Google Scholar 

  18. Kadosh, D. & Struhl, K. Targeted recruitment of the Sin3-Rpd3 histone deacetylase complex generates a highly localized domain of repressed chromatin in vivo. Mol. Cell Biol. 18, 5121 –5127 (1998).

    Article  CAS  Google Scholar 

  19. Ashraf, S. I. & Ip, Y. T. Transcriptional control: repression by local chromatin modification. Curr Biol. 8, R683–686 (1998).

    Article  CAS  Google Scholar 

  20. Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 ( 1998).

    Article  CAS  Google Scholar 

  21. Utley, R. T. et al. Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394, 498 –502 (1998).

    Article  CAS  Google Scholar 

  22. Imhof, A. & Wolffe, A. P. Transcription: gene control by targeted histone acetylation. Curr. Biol. 8, R422–424 (1998).

    Article  CAS  Google Scholar 

  23. Luger, K. & Richmond, T. J. The histone tails of the nucleosome. Curr. Opin. Genet. Dev. 8, 140– 146 (1998).

    Article  CAS  Google Scholar 

  24. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–62 (1999).

    CAS  Google Scholar 

  25. Monyer, H., Seeburg, P. H. & Wisden, W. Glutamate-operated channels: developmentally early and mature forms arise by alternative splicing. Neuron 6, 799–810 (1991).

    Article  CAS  Google Scholar 

  26. Sato, K., Kiyama, H. & Tohyama, M. The differential expression patterns of messenger RNAs encoding non-N-methyl-D-aspartate glutamate receptor subunits (GluR1-4) in the rat brain. Neuroscience 52, 515– 539 (1993).

    Article  CAS  Google Scholar 

  27. Yoshida, M., Kijima, M., Akita, M. & Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174– 17179 (1990).

    CAS  PubMed  Google Scholar 

  28. Doetzlhofer, A. et al. Histone deacetylase 1 can repress transcription by binding to Sp1. Mol. Cell Biol. 19, 5504– 5511 (1999).

    Article  CAS  Google Scholar 

  29. Zhang, W. & Bieker, J. J. Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proc. Natl. Acad. Sci. USA 95, 9855–9860 (1998).

    Article  CAS  Google Scholar 

  30. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  Google Scholar 

  31. Boyes, J., Byfield, P., Nakatani, Y. & Ogryzko, V. Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396, 594–598 (1998).

    Article  CAS  Google Scholar 

  32. Van Lint, C., Emiliani, S. & Verdin, E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr. 5, 245–253 ( 1996).

    CAS  PubMed  Google Scholar 

  33. Cousens, L. S., Gallwitz, D. & Alberts, B. M. Different accessibilities in chromatin to histone acetylase. J. Biol. Chem. 254, 1716– 1723 (1979).

    CAS  PubMed  Google Scholar 

  34. Gray, S. G. & Ekstrom, T. J. Effects of cell density and trichostatin A on the expression of HDAC1 and p57Kip2 in Hep 3B cells. Biochem. Biophys. Res. Commun. 245, 423–427 (1998).

    Article  CAS  Google Scholar 

  35. Tapia-Ramirez, J., Eggen, B. J., Peral-Rubio, M. J., Toledo-Aral, J. J. & Mandel, G. A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter. Proc. Natl. Acad. Sci. USA 94, 1177–1182 (1997).

    Article  CAS  Google Scholar 

  36. Thiel, G., Lietz, M. & Cramer, M. Biological activity and modular structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes. J. Biol. Chem. 273, 26891–26899 (1998).

    Article  CAS  Google Scholar 

  37. Leichter, M. & Thiel, G. Transcriptional repression by the zinc finger protein REST is mediated by titratable nuclear factors. Eur. J. Neurosci. 11, 1937–1946 (1999).

    Article  CAS  Google Scholar 

  38. Andres, M. E. et al. CoREST: A functional corepressor required for regulation of neural-specific gene expression. Proc. Natl. Acad. Sci. USA 96, 9873–9878 (1999).

    Article  CAS  Google Scholar 

  39. Carmen, A. A., Rundlett, S. E. & Grunstein, M. HDA1 and HDA3 are components of a yeast histone deacetylase (HDA) complex. J. Biol. Chem. 271, 15837 –15844 (1996).

    Article  CAS  Google Scholar 

  40. Emiliani, S., Fischle, W., Van Lint, C., Al-Abed, Y. & Verdin, E. Characterization of a human RPD3 ortholog, HDAC3. Proc. Natl. Acad. Sci. USA 95, 2795–2800 (1998).

    Article  CAS  Google Scholar 

  41. Grozinger, C. M., Hassig, C. A. & Schreiber, S. L. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. USA 96, 4868–4873 (1999).

    Article  CAS  Google Scholar 

  42. Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).

    Article  CAS  Google Scholar 

  43. Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl. Acad. Sci. USA 95, 3519–3524 (1998).

    Article  CAS  Google Scholar 

  44. Sowa, Y. et al. Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. Biochem. Biophys. Res. Commun. 241, 142–150 (1997).

    Article  CAS  Google Scholar 

  45. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re- expression of genes silenced in cancer. Nat. Genet. 21, 103–107 (1999).

    Article  CAS  Google Scholar 

  46. Coffee, B., Zhang, F., Warren, S. T. & Reines, D. Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. Nat. Genet. 22, 98–101 ( 1999).

    Article  CAS  Google Scholar 

  47. Prince, H. K., Conn, P. J., Blackstone, C. D., Huganir, R. L. & Levey, A. I. Down-regulation of AMPA receptor subunit GluR2 in amygdaloid kindling. J. Neurochem 64, 462–465 (1995).

    Article  CAS  Google Scholar 

  48. Pellegrini-Giampietro, D. E., Zukin, R. S., Bennett, M. V., Cho, S. & Pulsinelli, W. A. Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats. Proc. Natl. Acad. Sci. USA 89, 10499–10503 (1992).

    Article  CAS  Google Scholar 

  49. Friedman, L. K. et al. Kainate-induced status epilepticus alters glutamate and GABA A receptor gene expression in adult rat hippocampus: an in situ hybridization study. J. Neurosci. 14, 2697– 2707 (1994).

    Article  CAS  Google Scholar 

  50. Pollard, H., Heron, A., Moreau, J., Ben-Ari, Y. & Khrestchatisky, M. Alterations of the GluR-B AMPA receptor subunit flip/flop expression in kainate-induced epilepsy and ischemia. Neuroscience 57, 545–554 ( 1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Rick Kahn for the mouse anti-myc antibody, David Anderson for the mouse anti-REST antibody, Stuart Schrieber for the HDAC constructs, Gerald Thiel for the myc-REST and Gal4-REST constructs, Gail Mandel for the type II sodium-channel promoter and Nancy F. Ciliax for neuronal cultures. We thank Jerry Boss, John Lucchesi and Steve Warren for comments on an early version of the manuscript. Supported by NIH grant NS36604 (R.D.) and an NRSA (S.J.M.).

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Correspondence to Raymond Dingledine.

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Huang, Y., Myers, S. & Dingledine, R. Transcriptional repression by REST: recruitment of Sin3A and histone deacetylase to neuronal genes. Nat Neurosci 2, 867–872 (1999). https://doi.org/10.1038/13165

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