Local epigenetic reprograming induced by G-quadruplex ligands
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Balasubramanian, S. (2017). Local epigenetic reprograming induced by G-quadruplex ligands. Nature Chemistry, 9 1110-1117. https://doi.org/10.1038/nchem.2828
DNA and histone modifications regulate transcriptional activity and thus represent valuable targets to reprogram the activity of genes. Current epigenetic therapies target the machinery that regulates these modifications, leading to global transcriptional reprogramming with the potential for extensive undesired effects. Epigenetic information can also be modified as a consequence of disrupting processive DNA replication. Here, we demonstrate that impeding replication by small-molecule-mediated stabilization of G-quadruplex nucleic acid secondary structures triggers local epigenetic plasticity. We report the use of the BU-1 locus of chicken DT40 cells to screen for small molecules able to induce G-quadruplex-dependent transcriptional reprogramming. Further characterization of the top hit compound revealed its ability to induce a dose-dependent inactivation of BU-1 expression in two steps: the loss of H3K4me3 and then subsequent DNA cytosine methylation, changes that were heritable across cell divisions even after the compound was removed. Targeting DNA secondary structures thus represents a potentially new approach for locus-specific epigenetic reprogramming.
Work in the Sale group is supported by a central grant to the LMB by the MRC (U105178808). B.R. is supported by an LMB/AstraZeneca BlueSkies postdoctoral fellowship (BSF5). S.B. is a Wellcome Trust Senior Investigator (grant no. 099232/z/12/z). The Balasubramanian group is supported by a European Research Council Advanced Grant (no. 339778) and receives core funding (C14303/A17197) and programme funding (C9681/A18618) from Cancer Research UK.
Cancer Research UK (18618)
Cancer Research UK (CB4330)
Wellcome Trust (099232/Z/12/Z)
European Research Council (339778)
External DOI: https://doi.org/10.1038/nchem.2828
This record's URL: https://www.repository.cam.ac.uk/handle/1810/265087