Letter | Published:

Coordinated histone modifications mediated by a CtBP co-repressor complex

Abstract

The transcriptional co-repressor CtBP (C-terminal binding protein) is implicated in tumorigenesis because it is targeted by the adenovirus E1A protein during oncogenic transformation1. Genetic studies have also identified a crucial function for CtBP in animal development2. CtBP is recruited to DNA by transcription factors that contain a PXDLS motif3,4, but the detailed molecular events after the recruitment of CtBP to DNA and the mechanism of CtBP function in tumorigenesis are largely unknown. Here we report the identification of a CtBP complex that contains the essential components for both gene targeting and coordinated histone modifications, allowing for the effective repression of genes targeted by CtBP. Inhibiting the expression of CtBP and its associated histone-modifying activities by RNA-mediated interference resulted in alterations of histone modifications at the promoter of the tumour invasion suppressor gene E-cadherin and increased promoter activity in a reporter assay. These findings identify a molecular mechanism by which CtBP mediates transcriptional repression and provide insight into CtBP participation in oncogenesis.

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References

  1. 1

    Boyd, J. M. et al. A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J. 12, 469–478 (1993)

  2. 2

    Chinnadurai, G. CtBP family proteins: More than transcriptional corepressors. BioEssays 25, 9–12 (2003)

  3. 3

    Nibu, Y., Zhang, H. & Levine, M. Interaction of short-range repressors with Drosophila CtBP in the embryo. Science 280, 101–104 (1998)

  4. 4

    Chinnadurai, G. CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol. Cell 9, 213–224 (2002)

  5. 5

    Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M. & Nakatani, Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296, 1132–1136 (2002)

  6. 6

    Postigo, A. A. & Dean, D. C. ZEB represses transcription through interaction with the corepressor CtBP. Proc. Natl Acad. Sci. USA 96, 6683–6688 (1999)

  7. 7

    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)

  8. 8

    Sewalt, R. G., Gunster, M. J., van der Vlag, J., Satijn, D. P. & Otte, A. P. C-terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate Polycomb proteins. Mol. Cell. Biol. 19, 777–787 (1999)

  9. 9

    Lahn, B. T. & Page, D. C. Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nature Genet. 21, 429–433 (1999)

  10. 10

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

  11. 11

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

  12. 12

    Schimitz, F., Konigstorfer, A. & Südhof, T. C. RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function. Neuron 28, 857–872 (2000)

  13. 13

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

  14. 14

    Zhang, Y. & Reinberg, D. Transcriptin regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001)

  15. 15

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

  16. 16

    Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

  17. 17

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001)

  18. 18

    Comjin, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001)

  19. 19

    Grooteclaes, M. L. & Frisch, S. M. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19, 3823–3828 (2000)

  20. 20

    Sui, G. C. et al. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl Acad. Sci. USA 99, 5515–5520 (2002)

  21. 21

    Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996)

  22. 22

    Collins, C. et al. Positional cloning of ZNF217 and NABC1: genes amplified at 20q13.2 and overexpressed in breast carcinoma. Proc. Natl Acad. Sci. USA 95, 8703–8708 (1998)

  23. 23

    Satijin, D. P. et al. Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis. Mol. Cell. Biol. 17, 6076–6806 (1997)

  24. 24

    Kumar, V. et al. Transcription corepressor CtBP is an NAD+-regulated dehydrogenase. Mol. Cell 10, 857–869 (2002)

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Acknowledgements

We thank G. Gill, M. Greenberg and F. Winston for a critical reading of this manuscript, J. Parvin for advice, G. Chinnadurai for the CtBP1 cDNA, Y. Zhang for the glutathione-S-transferase–histone H3 fusion proteins, A. Otte and S. Tronick for antibodies, P. Silver for the parental retroviral vector, and D. Chen and S. Gygi for mass spectrometric analysis of the CtBP1 complex. Yu.S. was supported by a Program in Cancer Biology Training Grant from the National Cancer Institute. This work was supported by a grant from the NIH to Y.S.

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Correspondence to Yang Shi.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1 (PDF 89 kb)

Supplementary Figure 2 (PDF 124 kb)

Supplementary Figure 3 (PDF 144 kb)

Supplementary Figure 4 (PDF 109 kb)

Supplementary Table 1 (PDF 7 kb)

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Further reading

Figure 1: Purification and mass spectrometric analysis of polypeptides associated with CtBP1.
Figure 2: Characterization of a CtBP core complex.
Figure 3: Enzymatic activities in the CtBP complex.
Figure 4: G9a and EuHMT are involved in CtBP-mediated repression.
Figure 5: ChIP analysis of histone modifications at the endogenous E-cad promoter.

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