Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chromatin crosstalk in development and disease: lessons from REST

Key Points

  • Enzymes that modify chromatin have an important role in the regulation of gene transcription. Often, these enzymes exist in the cell as part of larger complexes with other enzymes that provide complementary activities. Studies of the corepressor complexes that are recruited by the repressor element 1-silencing transcription factor (REST) have helped to identify functional interdependencies of some of these enzymes.

  • REST can recruit multiple corepressor complexes through independent domains resulting in either short-term transcriptional repression or long-term gene silencing. Recruitment of some complexes is cell- and gene-specific, whereas recruitment of others is influenced by intracellular signals.

  • Perturbation of REST is associated with several human diseases, including some neuronal and cardiovascular disorders, and cancer.

  • Bioinformatic analysis has predicted a genome-wide set of REST-binding sites and a comprehensive list of potential target genes. These data have been used successfully to predict some REST functions and identify potential therapeutic targets for REST-associated diseases.

  • Investigations of REST and its associated corepressors have provided insight into the coordination of enzymatic activities that modify chromatin and affect gene transcription. These studies make significant contributions to our understanding of chromatin changes and gene regulation in health and disease.

Abstract

Protein complexes that contain chromatin-modifying enzymes have an important role in regulating gene expression. Recent studies have shown that a single transcription factor, the repressor element 1-silencing transcription factor (REST), can act as a hub for the recruitment of multiple chromatin-modifying enzymes, uncovering interdependencies among individual enzymes that affect gene regulation. Research into the function of REST and its corepressors has provided novel insight into how chromatin-modifying proteins cooperate, and how alterations in this function cause disease. These mechanisms will be relevant to the combinatorial functioning of modular transcriptional regulators that work together to regulate a common promoter; they should also identify targets for potential therapies for a range of human diseases.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: REST corepressors.
Figure 2: Histone modifications and the repressor element 1-silencing transcription factor (REST) complex.

References

  1. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Stevely, W. S. & Stocken, L. A. Phosphorylation of rat-thymus histone. Biochem. J. 100, 20C–21C (1966).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Sung, P., Prakash, S. & Prakash, L. The RAD6 protein of Saccharomyces cerevisiae polyubiquitinates histones, and its acidic domain mediates this activity. Genes Dev. 2, 1476–1485 (1988).

    CAS  Article  PubMed  Google Scholar 

  4. Shiio, Y. & Eisenman, R. N. Histone sumoylation is associated with transcriptional repression. Proc. Natl Acad. Sci. USA 100, 13225–13230 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Kuo, M. H. & Allis, C. D. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20, 615–626 (1998).

    CAS  Article  PubMed  Google Scholar 

  6. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000).

    CAS  Article  PubMed  Google Scholar 

  7. Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Gen. Dev. 12, 198–209 (2002).

    CAS  Article  Google Scholar 

  8. Gill, G. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18, 2046–2059 (2004).

    CAS  Article  PubMed  Google Scholar 

  9. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  11. 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). References 10 and 11 report the cloning of the gene that encodes REST.

    CAS  Article  PubMed  Google Scholar 

  12. Bessis, A., Champtiaux, N., Chatelin, L. & Changeux, J.-P. The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain. Proc. Natl Acad. Sci. USA 94, 5906–5911 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Kallunki, P., Edelman, G. M. & Jones, F. S. Tissue-specific expression of the l1 cell adhesion molecule is modulated by the neural restrictive silencer element. J. Cell Biol. 138, 1343–1354 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  Article  PubMed  Google Scholar 

  15. Lonnerberg, P., Schoenherr, C. J., Anderson, D. J. & Ibanez, C. F. Cell type-specific regulation of choline acetyltransferase gene expression. Role of the neuron-restrictive silencer element and cholinergic-specific enhancer sequences. J. Biol. Chem. 271, 33358–33365 (1996).

    CAS  Article  PubMed  Google Scholar 

  16. Mieda, M., Haga, T. & Saffen, D. W. Expression of the rat M4 muscarinic acetylcholine receptor gene is regulated by the neuron-restrictive silencer element/repressor element 1. J. Biol. Chem. 272, 5854–5860 (1997).

    CAS  Article  PubMed  Google Scholar 

  17. Mori, N., Schoenherr, C. J., Vandenberg, D. J. & Anderson, D. J. A common silencer element in the scg10 and type II Na+ channel genes binds a factor present in non-neuronal cells but not in neuronal cells. Neuron 9, 45–54 (1992). Together with reference 14, this paper identified the RE1 site as a repressor element in neuronal genes.

    CAS  Article  PubMed  Google Scholar 

  18. Wood, I. C., Roopra, A. & Buckley, N. J. Neural specific expression of the M4 muscarinic acetylcholine receptor gene is mediated by a re1/nrse-type silencing element. J. Biol. Chem. 271, 14221–14225 (1996).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Grimes, J. A. et al. The co-repressor mSin3A is a functional component of the rest-corest repressor complex. J. Biol. Chem. 275, 9461–9467 (2000).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  23. Naruse, Y., Aoki, T., Kojima, T. & Mori, N. Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proc. Natl Acad. Sci. USA 96, 13691–13696 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Roopra, A. et al. Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3–histone deacetylase complex. Mol. Cell. Biol. 20, 2147–2157 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. SET domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

    CAS  Article  PubMed  Google Scholar 

  26. Zhang, Q., Piston, D. W. & Goodman, R. H. Regulation of corepressor function by nuclear NADH. Science 295, 1895–1897 (2002).

    CAS  PubMed  Google Scholar 

  27. Roopra, A., Qazi, R., Schoenike, B., Daley, T. J. & Morrison, J. F. Localized domains of G9a-mediated histone methylation are required for silencing of neuronal genes. Mol. Cell 14, 727–738 (2004).

    CAS  Article  PubMed  Google Scholar 

  28. Garriga-Canut, M. et al. 2-deoxy-D-glucose reduces epilepsy progression by NRSF–CTBP-dependent metabolic regulation of chromatin structure. Nature Neurosci. 9, 1382–1387 (2006).

    CAS  Article  PubMed  Google Scholar 

  29. Shi, Y. et al. Coordinated histone modifications mediated by a CTBP co-repressor complex. Nature 422, 735–738 (2003).

    CAS  Article  PubMed  Google Scholar 

  30. Zhao, L. J., Subramanian, T. & Chinnadurai, G. Changes in C-terminal binding protein 2 (CTBP2) corepressor complex induced by E1A and modulation of E1A transcriptional activity by CTBP2. J. Biol. Chem. 281, 36613–36623 (2006).

    CAS  Article  PubMed  Google Scholar 

  31. Lee, M. G., Wynder, C., Cooch, N. & Sheikhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005).

    CAS  Article  PubMed  Google Scholar 

  32. Shi, Y.-J. et al. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 1–8 (2005). Together with reference 69, this work revealed an interplay between histone deacetylation and histone demethylation.

    Article  CAS  Google Scholar 

  33. Zhang, Y. et al. SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex. Mol. Cell 1, 1021–1031 (1998).

    CAS  Article  PubMed  Google Scholar 

  34. Alland, L. et al. Identification of mammalian SDS3 as an integral component of the Sin3/histone deacetylase corepressor complex. Mol. Cell. Biol. 22, 2743–2750 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Fleischer, T. C., Yun, U. J. & Ayer, D. E. Identification and characterization of three new components of the mSin3A corepressor complex. Mol. Cell. Biol. 23, 3456–3467 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Nakagawa, Y. et al. Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes. J. Mol. Cell. Cardiol. 41, 1010–1022 (2006).

    CAS  Article  PubMed  Google Scholar 

  37. You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST human histone deactylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004). The first report of a histone lysine demethylase.

    CAS  Article  PubMed  Google Scholar 

  39. Battaglioli, E. et al. REST repression of neuronal genes requires components of the hSWI.SNF complex. J. Biol. Chem. 277, 41038–41045 (2002). Identification of chromatin remodelling as a component of REST repression.

    CAS  Article  PubMed  Google Scholar 

  40. Lunyak, W. et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002).

    CAS  Article  PubMed  Google Scholar 

  41. Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. REST and its co-repressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005). This paper revealed a role for REST in long-term gene silencing during development.

    CAS  Article  PubMed  Google Scholar 

  42. 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). The first indication that REST is expressed in neurons.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Calderone, A. et al. Ischemic insults derepress the gene silencer REST in neurons destined to die. J. Neurosci. 23, 2112–2121 (2003). Evidence that REST expression is altered in disease states, and REST-mediated gene repression is pivotal to the cellular response.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Wood, I. C. et al. Interaction of the repressor element 1-silencing transcription factor (REST) with target genes. J. Mol. Biol. 334, 863–874 (2003).

    CAS  Article  PubMed  Google Scholar 

  45. 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. Mol. Brain Res. 72, 30–39 (1999).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  47. Shimojo, M., Paquette, A. J., Anderson, D. J. & Hersh, L. B. Protein kinase A regulates cholinergic gene expression in PC12 cells: REST4 silences the silencing activity of neuron restrictive silencer factor/REST. Mol. Cell. Biol. 19, 6788–6795 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Spencer, E. M. et al. Regulation and role of REST and REST4 variants in modulation of gene expression in in vivo and in vitro in epilepsy models. Neurobiol Dis. 24, 41–52 (2006).

    CAS  Article  PubMed  Google Scholar 

  49. Magin, A., Lietz, M., Cibelli, G. & Thiel, G. RE1 silencing transcription factor 4 (REST4) is neither a transcriptional repressor nor a de-repressor. Neurochem. Int. 40, 195–202 (2002).

    CAS  Article  PubMed  Google Scholar 

  50. Coulson, J. M., Edgson, J. L., Woll, P. J. & Quinn, J. P. A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker. Cancer Res. 60, 1840–1844 (2000).

    CAS  PubMed  Google Scholar 

  51. Ooi, L., Belyaev, N. D., Miyake, K., Wood, I. C. & Buckley, N. J. BRG1 chromatin remodeling activity is required for efficient chromatin binding by the transcriptional repressor rest and facilitates rest-mediated repression. J. Biol. Chem. 281, 38974–38980 (2006). This paper describes the mechanism by which a chromatin-remodelling enzyme can enhance transcriptional repression.

    CAS  Article  PubMed  Google Scholar 

  52. Agalioti, T., Chen, G. & Thanos, D. Deciphering the transcriptional histone acetylation code for a human gene. Cell 111, 381–392 (2002).

    CAS  Article  PubMed  Google Scholar 

  53. Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861. (1998).

    CAS  Article  PubMed  Google Scholar 

  54. 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).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  56. 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).

    CAS  Article  PubMed  Google Scholar 

  57. Yu, J., Li, Y., Ishizuka, T., Guenther, M. G. & Lazar, M. A. A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J. 22, 3403–3410 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. de la Serna, I. L. et al. MyoD targets chromatin remodeling complexes to the myogenin locus prior to forming a stable DNA-bound complex. Mol. Cell. Biol. 25, 3997–4009 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 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).

    CAS  Article  PubMed  Google Scholar 

  60. Murphy, D. J., Hardy, S. & Engel, D. A. Human SWI–SNF component BRG1 represses transcription of the c-fos gene. Mol. Cell. Biol. 19, 2724–2733 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Burkhart, B. A., Hebbar, P. B., Trotter, K. W. & Archer, T. K. Chromatin-dependent E1A activity modulates NF-κB RelA-mediated repression of glucocorticoid receptor-dependent transcription. J. Biol. Chem. 280, 6349–6358 (2005).

    CAS  Article  PubMed  Google Scholar 

  62. Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).

    CAS  Article  PubMed  Google Scholar 

  63. Tapia-Ramirez, J., Eggen, B. J. L., 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  65. Nomura, M., Uda-Tochio, H., Murai, K., Mori, N. & Nishimura, Y. The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix. J. Mol. Biol. 354, 903–915 (2005).

    CAS  Article  PubMed  Google Scholar 

  66. Ayer, D. E., Lawrence, Q. A. & Eisenman, R. N. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80, 767–776 (1995).

    CAS  Article  PubMed  Google Scholar 

  67. Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Bingham, A. J., Ooi, L., Kozera, L., White, E. & Wood, I. C. The repressor element 1-silencing transcription factor regulates cardiac specific gene expression using multiple chromatin modifying complexes. Mol. Cell. Biol. 27, 4082–4092 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Tan, W., Zheng, L., Lee, W. H. & Boyer, T. G. Functional dissection of transcription factor ZBRK1 reveals zinc fingers with dual roles in DNA-binding and BRCA1-dependent transcriptional repression. J. Biol. Chem. 279, 6576–6587 (2004).

    CAS  Article  PubMed  Google Scholar 

  70. Milne, T. A. et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107–1117 (2002).

    CAS  Article  PubMed  Google Scholar 

  71. Wynder, C., Hakimi, M. A., Epstein, J. A., Shilatifard, A. & Shiekhattar, R. Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nature Cell Biol. 7, 1113–1117 (2005).

    CAS  Article  PubMed  Google Scholar 

  72. Ueda, J., Tachibana, M., Ikura, T. & Shinkai, Y. Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CTBP. J. Biol. Chem. 281, 20120–20128 (2006).

    CAS  Article  PubMed  Google Scholar 

  73. Belyaev, N. D. et al. Distinct RE-1 silencing transcription factor-containing complexes interact with different target genes. J. Biol. Chem. 279, 556–561 (2004).

    CAS  Article  PubMed  Google Scholar 

  74. Peters, A. H. F. M. et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nature Genet. 30, 77 (2002).

    CAS  Article  PubMed  Google Scholar 

  75. Pokholok, D. K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122, 517–527 (2005).

    CAS  Article  PubMed  Google Scholar 

  76. Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse cells. Cell 120, 169–181 (2005).

    CAS  Article  PubMed  Google Scholar 

  77. Kuwahara, K. et al. NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J. 22, 6310–6321 (2003). This paper demonstrated that inhibition of REST function results in cardiac hypertrophy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Cheong, A. et al. Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation. Mol. Cell 20, 45–52 (2005). Identification of REST expression in vascular smooth muscle and its role in phenotypic switching.

    CAS  Article  PubMed  Google Scholar 

  79. Yang, M. et al. Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol. Cell 23, 377–387 (2006).

    CAS  Article  PubMed  Google Scholar 

  80. Hartman, H. B., Yu, J., Alenghat, T., Ishizuka, T. & Lazar, M. A. The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep. 6, 445–451 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Vermeulen, M. et al. A feed-forward repression mechanism anchors the Sin3/histone deacetylase and N-CoR/SMRT corepressors on chromatin. Mol. Cell. Biol. 26, 5226–5236 (2006). This paper demonstrated that repression by the mSin3 complex is influenced by H3 acetylation but not H4 acetylation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Greenway, D. J., Street, M., Jeffries, A. & Buckley, N. J. REST maintains a repressive chromatin environment in embryonic hippocampal neural stem cells. Stem Cells 25, 354–363 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Miller, C. A. & Sweatt, J. D. Covalent modification of DNA regulates memory formation. Neuron 53, 857–869 (2007).

    CAS  Article  PubMed  Google Scholar 

  84. Jepsen, K. et al. Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102, 753–763 (2000).

    CAS  Article  PubMed  Google Scholar 

  85. Westbrook, T. F. et al. A genetic screen for candidate tumor supressors identifies REST. Cell 121, 837–848 (2005).

    CAS  Article  PubMed  Google Scholar 

  86. Leung, T. H., Hoffmann, A. & Baltimore, D. One nucleotide in a κB site can determine cofactor specificity for NF-κB dimers. Cell 118, 453 (2004).

    CAS  Article  PubMed  Google Scholar 

  87. Johnson, R. et al. Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication. Nucl. Acids Res. 34, 3862–3877 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Murai, K., Naruse, Y., Shaul, Y., Agata, Y. & Mori, N. Direct interaction of NRSF with TBP: chromatin reorganization and core promoter repression for neuron-specific gene transcription. Nucleic Acids Res. 32, 3180–3189 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Yeo, M. et al. Small CTD phosphatases function in silencing neuronal gene expression. Science 307, 596–600 (2005).

    CAS  Article  PubMed  Google Scholar 

  90. Muscat, G. E., Burke, L. J. & Downes, M. The corepressor N-CoR and its variants RIP13a and RIP13δ1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70. Nucleic Acids Res. 26, 2899–2907 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Bruce, A. W. et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc. Natl Acad. Sci. USA 101, 10458–10463 (2004). The first genome-wide identification of RE1 sites.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Jones, N. C. & Pevzner, P. A. Comparative genomics reveals unusually long motifs in mammalian genomes. Bioinformatics 22, e236–e242 (2006).

    CAS  Article  PubMed  Google Scholar 

  93. Mortazavi, A., Thompson, E. C., Garcia, S. T., Myers, R. M. & Wold, B. Comparative genomics modeling of the NRSF/REST repressor network: from single conserved sites to genome-wide repertoire. Genome Res. 16, 1208–1221 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Wu, J. & Xie, X. Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol. 7, R85 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Conaco, C., Otto, S., Han, J. J. & Mandel, G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc. Natl Acad. Sci. USA 103, 2422–2427 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Bruce, A. W. et al. The transcriptional repressor REST is a critical regulator of the neurosecretory phenotype. J. Neurochem. 98, 1828–1840 (2006).

    CAS  Article  PubMed  Google Scholar 

  97. Pance, A., Livesey, F. J. & Jackson, A. P. A role for the transcriptional repressor REST in maintaining the phenotype of neurosecretory-deficient PC12 cells. J. Neurochem. 99, 1435–1444 (2006).

    CAS  Article  PubMed  Google Scholar 

  98. Hornstein, E. & Shomron, N. Canalization of development by microRNAs. Nature Genet. 38, S20–S24 (2006).

    CAS  Article  PubMed  Google Scholar 

  99. Kloosterman, W. P. & Plasterk, R. H. The diverse functions of microRNAs in animal development and disease. Dev. Cell 11, 441–450 (2006).

    CAS  Article  PubMed  Google Scholar 

  100. Visvanathan, J., Lee, S., Lee, B., Lee, J. W. & Lee, S.-K. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K. & Gage, F. H. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116, 779–793 (2004). This paper describes a novel non-coding RNA that is involved in regulating REST function in the developing nervous system.

    CAS  Article  PubMed  Google Scholar 

  102. Kloosterman, W. P. et al. Cloning and expression of new microRNAs from zebrafish. Nucleic Acids Res. 34, 2558–2569 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Lanz, R. B. et al. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97, 17–27 (1999).

    CAS  Article  PubMed  Google Scholar 

  104. Feng, J. et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20, 1470–1484 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Chen, Z.-F., Paquette, A. J. & Anderson, D. J. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nature Genet. 20, 136–142 (1998).

    CAS  Article  PubMed  Google Scholar 

  106. Olguin, P., Oteiza, P., Gamboa, E., Gomez-Skarmeta, J. L. & Kukuljan, M. RE-1 silencer of transcription/neural restrictive silencer factor modulates ectodermal patterning during Xenopus development. J. Neurosci. 26, 2820–2829 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. Armisen, R., Fuentes, R., Olguin, P., Cabrejos, M. E. & Kukuljan, M. Repressor element-1 silencing transcription/neuron-restrictive silencer factor is required for neural sodium channel expression during development of Xenopus. J. Neurosci. 22, 8347–8351 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Kuwahara, K. et al. The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes. Mol. Cell. Biol. 21, 2085–2097 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Hohl, M. & Thiel, G. Cell type-specific regulation of RE-1 silencing transcription factor (REST) target genes. Eur. J. Neurosci. 22, 2216–2230 (2005).

    Article  PubMed  Google Scholar 

  110. Paquette, A. J., Perez, S. E. & Anderson, D. J. Constitutive expression of the neuron-restrictive silencer factor (NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc. Natl Acad. Sci. USA 97, 12318–12323 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Majumder, S. REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle 5, 1929–1935 (2006).

    CAS  Article  PubMed  Google Scholar 

  112. Formisano, L. et al. Ischemic insults promote epigenetic reprogramming of mu opioid receptor expression in hippocampal neurons. Proc. Natl Acad. Sci. USA 104, 4170–4175 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. Zuccato, C. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genet. 35, 76–83 (2003).

    CAS  Article  PubMed  Google Scholar 

  114. Fuller, G. N. et al. Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16. Mol. Cancer Ther. 4, 343–349 (2005).

    CAS  PubMed  Google Scholar 

  115. Lawinger, P. et al. The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nature Med. 6, 826–831 (2000).

    CAS  Article  PubMed  Google Scholar 

  116. Su, X. et al. Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol. Cell. Biol. 26, 1666–1678 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Huynh, T. T. et al. Transcriptional regulation of phenylethanolamine N-methyltransferase in pheochromocytomas from patients with von Hippel–Lindau syndrome and multiple endocrine neoplasia type 2. Ann. NY Acad. Sci. 1073, 241–52 (2006).

    CAS  Article  PubMed  Google Scholar 

  118. Kohler, R. et al. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. Circulation 108, 1119–1125 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Stafstrom, C. E. Dietary approaches to epilepsy treatment: old and new options on the menu. Epilepsy Curr. 4, 215–222 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Impey, S. et al. Defining the CREB regulon: a genome wide analysis of transcription factor regulatory regions. Cell 119, 1041–1054 (2004).

    CAS  PubMed  Google Scholar 

  121. Boyer, L. A. et al. Core transcriptional regulatory circiutry in human embryonic stem cells. Cell 122, 947–956 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Loh, Y. H. et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genet. 38, 431–440 (2006).

    CAS  Article  PubMed  Google Scholar 

  123. Ooi, L. An analysis of repressor element 1 silencing transcription factor interactions with its target genes. Thesis, Univ. Leeds (2005).

  124. Koenigsberger, C., Chicca, J. J., 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Kojima, T., Murai, K., Naruse, Y., Takahashi, N. & Mori, N. Cell-type non-selective transcription of mouse and human genes encoding neural-restrictive silencer factor. Brain Res. Mol. Brain Res. 90, 174–186 (2001).

    CAS  Article  PubMed  Google Scholar 

  126. Nishihara, S., Tsuda, L. & Ogura, T. The canonical Wnt pathway directly regulates NRSF/REST expression in chick spinal cord. Biochem. Biophys. Res. Commun. 311, 55–63 (2003).

    CAS  Article  PubMed  Google Scholar 

  127. Stormo, G. D. DNA binding sites: representation and discovery. Bioinformatics 16, 16–23 (2000).

    CAS  Article  PubMed  Google Scholar 

  128. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Boyes for helpful comments and discussions on the manuscript. Work in the Wood laboratory is supported by the British Heart Foundation and the European Commission.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Lezanne Ooi or Ian C. Wood.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Huntington disease

von Hippel–Lindau syndrome

FURTHER INFORMATION

Lezanne Ooi's homepage

Ian Wood's homepage

RE1 database from REF 91

RE1 database from REF 87

RE1 database from REF 93

 RE1 database from REF 94

Glossary

Regulated secretion

A process by which proteins and neurotransmitters are stored in secretory vesicles and released only in response to external stimuli such as hormones.

Hippocampus

An anatomical region of the brain, with a shape likened to that of a seahorse, that is located adjacent to the ventricles and is important for memory formation.

Ischaemia

An insufficient supply of blood to an organ, often resulting from an artery blockage or constriction.

AMPA receptors

Ligand-gated cation channels that are responsive to excitatory amino acids such as glutamate, and are composed of four individual subunits as a homo- or heterotetramer. The presence of the glutamate receptor 2 (GluR2) subunit prevents the permeation of calcium through the channel.

Inhibitory interneurons

Local circuit neurons that form connections with other neurons and release inhibitory neurotransmitters such as GABA (γ-aminobutyric acid), which act to suppress activity of the target neuron.

Striatum

A subcortical anatomical region of the brain, named for its striated appearance, that is important in coordination of movement.

Neural crest

An embryological region of dividing cells that lies adjacent to the neural tube. Cells from the neural crest migrate away and ultimately give rise to many cell types, including the neurons and glia of the peripheral nervous system, skeletal muscle and smooth muscle cells, and chromaffin cells.

Constitutive secretion

A process by which proteins and neurotransmitters are secreted by exocytosis without any requirement for external stimuli.

In-stent restenosis

The narrowing of an artery caused by the insertion of a metal cylinder (stent) intended to increase the diameter of a blocked artery, most often the result of vascular smooth muscle cell proliferation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ooi, L., Wood, I. Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet 8, 544–554 (2007). https://doi.org/10.1038/nrg2100

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2100

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing