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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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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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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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Shi, Y., Sawada, Ji., Sui, G. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003). https://doi.org/10.1038/nature01550

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