Nature 387, 43 - 48 (01 May 1997); doi:10.1038/387043a0

A complex containing N-CoR, mSln3 and histone deacetylase mediates transcriptional repression

Thorsten Heinzel^*, Robert M. Lavinsky^*†, Tina-Marie Mullen^‡, Mats Söderström^§, Carol D. Laherty, Joseph Torchia^*, Wen-Ming Yang^¶, Gyan Brard^§, Sally D. Ngo^§, James R. Davie , Edward Seto^¶, Robert N. Eisenman, David W. Rose^‡, Christopher K. Glass^§ & Michael G. Rosenfeld^*

^* Howard Hughes Medical Institute, ^† UCSD Graduate Program in Biology, ^‡ Whittier Diabetes Program, and ^§ Cellular and Molecular Medicine, Department and School of University of California, San Diego, La Jolla, California 92093-0648, USA
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA
^¶ H. Lee Moffitt Cancer Center and Research Institute, Department of Medical Microbiology and Immunology, University of South Florida, Tampa, Florida 33612, USA
Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Manitoba, R3E OW3, Canada

Transcriptional repression by nuclear receptors has been correlated to binding of the putative co-repressor, N-CoR. A complex has been identified that contains N-CoR, the Mad presumptive co-repressor mSin3, and the histone deacetylase mRPD3, and which is required for both nuclear receptor- and Mad-dependent repression, but not for repression by transcription factors of the ets-domain family. These data predict that the ligand-induced switch of heterodimeric nuclear receptors from repressor to activator functions involves the exchange of complexes containing histone deacetylases with those that have histone acetylase activity.

1. Chambon, P. The retinoid signaling pathway: molecular and genetic analyses. Semin. Cell Biol. 5, 115−125 (1994). | Article | PubMed | ChemPort |
2. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835−839 (1995). | Article | PubMed | ISI | ChemPort |
3. Wong, J., Shi, Y. & Wolffe, A. P. A role for nucleosome assembly in both silencing and activation of the Xenopus TRBA gene by the thyroid hormone receptor. Genes Dev. 9, 2696−2711 (1995). | PubMed | ISI | ChemPort |
4. Glass, C. K., Holloway, J. M., Devary, O. V. & Rosenfeld, M. G. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell 54, 313−323 (1988). | Article | PubMed | ISI | ChemPort |
5. Baniahmad, A., Kohne, A. C. & Renkawitz, R. A transferable silencing domain is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor. EMBO J. 11, 1015−1023 (1992). | PubMed | ISI | ChemPort |
6. Baniahmad, A. et al. Interaction of human thyroid hormone receptor beta with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. Proc. Natl Acad. Sci. USA 90, 8832−8836 (1993). | PubMed | ChemPort |
7. Baniahmad, A. et al. The t4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing. Mol. Cell. Biol. 15, 76−86 (1995). | PubMed | ISI | ChemPort |
8. Hörlein, A. J. et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377, 397−404 (1995). | Article | PubMed | ISI | ChemPort |
9. Kurokawa, R. et al. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377, 451−454 (1995). | Article | PubMed | ISI | ChemPort |
10. Zamir, I. et al. A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Mol. Cell. Biol. 16, 5458−5465 (1996). | PubMed | ISI | ChemPort |
11. Ayer, D. E., Kretzner, L. & Eisenman, R. N. Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell 72, 211−222 (1993). | Article | PubMed | ISI | ChemPort |
12. Ayer, D. E. & Eisenman, R. N. A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev. 7, 2110−2119 (1993). | PubMed | ISI | ChemPort |
13. Hurlin, P. J., Ayer, D. E., Grandori, C. & Eisenman, R. N. The Max transcription factor network. Cold Spring Harb. Symp. Quant. Biol. 59, 109−116 (1994). | PubMed | ChemPort |
14. Ayer, D. E., Lawrence, Q. A. & Eisenman, R. N. Mac-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80, 767−776 (1995). | Article | PubMed | ISI | ChemPort |
15. Schreiber-Agus, N. et al. An amino-terminal domain of Mxil mediates anti-Myconcogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80, 777−786 (1995). | Article | PubMed | ChemPort |
16. Ayer, D. E., Laherty, C. D., Lawrence, Q. A., Armstrong, A. & Eisenman, R. N. Mad proteins contain a dominant transcription repression domain. Mol. Cell. Biol. 16, 5772−5781 (1996). | PubMed | ISI | ChemPort |
17. Nasmyth, K., Stillman, D. & Kipling, D. Both positive and negative regulators of HO transcription are required for mother-cell-specific mating type switching. Cell 48, 579−587 (1987). | Article | PubMed | ISI | ChemPort |
18. Sternber, P. W., Stern, M. J., Clark, I. & Herskowitz, I. Activation of the yeast HO gene by release from multiple negative controls. Cell 48, 567−577 (1987). | Article | PubMed | ISI | ChemPort |
19. Wang, H., Clark, I., Nicholson, P. R., Herskowitz, I. & Stillman, D. J. The S. cerevisiae SIN3 gene, a negative regulator of HO, contains four paired amphipathic helical motifs. Mol. Cell. Biol. 10, 5927−5936 (1990). | PubMed | ISI | ChemPort |
20. Vidal, M., Strich, R., Esposito, R. E. & Gaber, R. F. RPD1 is required for maximal activation and repression of diverse yeast genes. Mol. Cell. Biol. 11, 6306−6316 (1991). | PubMed | ISI | ChemPort |
21. Vidal, M. & Gaber, R. F. RPD3 encodes a second factor required to achieve maximal positive and negative regulation. Mol. Cell. Biol. 11, 6317−6327 (1991). | PubMed | ISI | ChemPort |
22. Wang, H. & Stillman, D. Transcriptional repression in S. cerevisiae by a SIN3-LexA fusion protein. Mol. Cell. Biol. 13, 1805−1814 (1993). | PubMed | ISI | ChemPort |
23. Nawaz, Z. et al. The yeast SIN3 gene product negatively regulates the activity of the human progesterone receptor. Mol. Gen. Genet. 245, 724−733 (1994). | Article | PubMed | ChemPort |
24. Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408−411 (1996). | PubMed | ISI | ChemPort |
25. Yoshida, M., Horinouchi, S. & Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. BioEssays 17, 423−430 (1995). | Article | PubMed | ISI | ChemPort |
26. Yang, W.-M., Inouye, C., Zeng, Y., Bearss, D. & Seto, E. Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl Acad. Sci. USA 93, 12845−12850 (1996). | Article | PubMed | ChemPort |
27. Rose , D. W., McCabe, G., Feramisco, J. R. & Adler, M. Expression of c-fos and AP-1 activity in senescent human fibroblasts is not sufficient for DNA synthesis. J. Cell Biol. 119, 1405−1411 (1992). | Article | PubMed | ISI | ChemPort |
28. Sgouras, D. N. et al. ERF: an ETS-domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14, 4781−4793 (1995). | PubMed | ISI | ChemPort |
29. O'Neill, E. M., Rebay, I., Tijian, R. & Rubin, G. M. The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell 78, 137−147 (1994). | PubMed | ChemPort |
30. Chen, J. D. & Evans, R. M. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377, 454−457 (1995). | Article | PubMed | ISI | ChemPort |
31. Rundlett, S. E. et al. HDA I and RPD3 are members of distinct yeast histone deacetylase complexes. Proc. Natl Acad. Sci. USA 93, 14503−14508 (1996). | Article | PubMed | ChemPort |
32. Gray, S. & Levine, M. Transcriptional repression in development. Curr. Opin. Cell Biol. 8, 358−364 (1996). | Article | PubMed | ISI | ChemPort |
33. Kingston, R. E., Bunker, C. A. & Imbalzano, A. N. Repression and activation by multiprotein complexes that alter chromatin structure. Genes Dev. 10, 905−920 (1996). | ChemPort |
34. Svaren, J. & Horz, W. Regulation of gene expression by nucleosomes. Curr Opin. Genet. Dev. 6, 164−170 (1996). | Article | PubMed | ISI | ChemPort |
35. Hanna-Rose, W. & Hansen, U. Active repression mechanisms of eukaryotic transcription repressors. Trends Genet. 12, 229−234 (1996). | Article | PubMed | ChemPort |
36. Johnson, A. D. The price of repression. Cell 81, 655−658 (1995). | Article | PubMed | ISI | ChemPort |
37. Peterson, C. L. Multiple SWitches to turn on chromatin. Curr. Opin. Genet. Dev., 6, 171−175 (1996). | Article | PubMed | ISI | ChemPort |
38. Roth, S. Y. & Allis, C. D. Histone acetylation and chromatin assembly: A single escort, multiple dances? Cell 87, 5−8 (1996). | Article | PubMed | ISI | ChemPort |
39. Wolffe, A. P. & Pruss, D. Targeting chromatin disruption. Cell 84, 817−819 (1996). | Article | PubMed | ISI | ChemPort |
40. Lee, D. Y., Hayes, J. J., Pruss, D. & Wolffe, A. P. A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell 72, 73−84 (1993). | Article | PubMed | ISI | ChemPort |
41. Scol, W., Mahon, M. J., Lee, Y. K. & Moore, D. D. Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR. Mol. Endocrinol. 10, 1646−1655 (1996). | Article | PubMed | ISI | ChemPort |
42. Keleher, C. A., Redd, M., Schultz, J., Carlson, M. & Johnson, A. D. SSN6-Tup 1 is a general repressor of transcription in yeast. Cell 68, 709−719 (1992). | Article | PubMed | ISI | ChemPort |
43. Almouzni, G., Khochbin, S., Dimitrov, S. & Wolffe, A. P. Histone acetylation influences both gene expression and development of Xenopus laevis. Dev. Biol. 165, 654−659 (1994). | Article | PubMed | ISI | ChemPort |
44. Ogryzko, V. V., Schlitz, R. L., Russanova, V., Howard, B. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953−959 (1996). | Article | PubMed | ISI | ChemPort |
45. Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641−643 (1996). | Article | PubMed | ISI | ChemPort |
46. Kamei, Y. et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 1−12 (1996). | Article | PubMed |
47. Hendzel, M. J., Delcuve, G. P. & Davie, J. R. Histone deacetylase is a component of the internal nuclear matrix. J. Biol. Chem. 266, 21936−21942 (1991). | PubMed | ISI | ChemPort |
48. Li, W., Chen, H. Y. & Davie, J. R. Properties of chicken erythrocyte histone deacetylase associated with the nuclear matrix. Biochem. J. 314, 631−637 (1996). | PubMed | ISI | ChemPort |
49. Oñate, S. A., Tsai, S. Y., Tsai, M.−J. & O'Malley, B. W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354−1357 (1995). | PubMed | ISI | ChemPort |
50. Yang, X.-J., Ogryzko, V. V., Nishikawa, J.-I., Howard, B. H. & Nakatani, Y. Nature 382, 319−324 (1996). | Article | PubMed | ISI | ChemPort |
51. Laherty, C. D. et al. Cell (in the press).