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H2A.Z-dependent crosstalk between enhancer and promoter regulates Cyclin D1 expression

Oncogene volume 32, pages 4243–4251 (2013)Cite this article

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Abstract

H2A.Z association with specific genomic loci is thought to contribute to a chromatin structure that promotes transcription activation. Acetylation of H2A.Z at promoters of oncogenes has been linked to tumorigenesis. The mechanism is unknown. Here, we show that in triple negative breast cancer cells, H2A.Z bound to the promoter of the constitutively, weakly expressed cyclin D1 oncogene (CCND1), a key regulator of cellular proliferation. Depleting the pool of H2A.Z stimulated transcription of CCND1 in the absence of its cognate transcription factor, the estrogen receptor (ER). During activation of CCND1, H2A.Z was released from the transcription start site (TSS) and downstream enhancer (enh2) sequences. Concurrently, acetylation of H2A.Z, H3 and H4 at the TSS was increased but only H2A.Z was acetylated at enh2. Acetylation of H2A.Z required the Tip60 acetyltransferase to be associated with the activated CCND1 on both TSS and enh2 sites. Depletion of Tip60 prevented CCND1 activation. Chromosome conformation capture experiments (3C) revealed specific contacts between the TSS and enh2 chromatin regions. These results suggest that release of a histone H2A.Z-mediated repression loop activates CCND1 for transcription. Our findings open new avenues for controlling and understanding aberrant gene expression associated with tumorigenesis.

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Acknowledgements

We would like to thank Dr Didier Trouche for the Tip60 expressing vector and insightful discussions, J Eeckhoute, Lille for sharing unpublished work, and David Laperriere, IRIC, Montreal, for expert advice on genome database use. This work was supported by the Ligue Nationale Contre le Cancer (fellowship to LB), the Institut National du Cancer (INCa grant no. 34696) and the Fondation pour la Recherche Médicale (FRM, fellowship to MD).

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  1. Laboratoire de Biologie Moléculaire Eucaryote (LBME), University of Toulouse, Toulouse, France

    M Dalvai, L Bellucci, L Fleury, A-C Lavigne, F Moutahir & K Bystricky

  2. UMR 5099 CNRS,

    M Dalvai, L Bellucci, L Fleury, A-C Lavigne, F Moutahir & K Bystricky

  3. LBME, Toulouse, France

    M Dalvai, L Bellucci, L Fleury, A-C Lavigne, F Moutahir & K Bystricky

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  1. M Dalvai
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Dalvai, M., Bellucci, L., Fleury, L. et al. H2A.Z-dependent crosstalk between enhancer and promoter regulates Cyclin D1 expression. Oncogene 32, 4243–4251 (2013). https://doi.org/10.1038/onc.2012.442

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