Abstract
Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatiotemporal control. Here we present a generalizable approach, referred to as 'chemo-optical modulation of epigenetically regulated transcription' (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may be translated into new therapeutic strategies for diseases where conditional and selective epigenome modulation is required.
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Acknowledgements
We thank members of the Haggarty and Mazitschek laboratories and T. Pezeril for their constructive feedback throughout the project. We acknowledge financial support from the US National Institutes of Health (R01NS088209 R.M. and S.J.H., P50CA086355 R.M., R01DA028301 S.J.H., T32-CA079443 J.A.H.). S.J.H. is supported through funding from the Tau Consortium, Bluefield Consortium for Frontotemporal Dementia and Pitt-Hopkins Research Foundation. The computations in this paper were run on the Odyssey cluster supported by the Faculty of Arts and Sciences, Division of Science, Research Computing Group at Harvard University. We thank S. Johnston for acquiring the high-resolution mass spectra, and members of the Arduino development team and the open-source Maker Movement.
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Contributions
R.M. and S.J.H. conceived of the idea for the study; designed, directed and interpreted experiments, and wrote the manuscript; R.M. designed, synthesized and characterized inhibitors, and designed and built LED array; S.A.R. planned and performed cell-based assays, high-content image analysis, analyzed data and helped prepare the manuscript; B.G. synthesized inhibitors, planned and performed cell-based assays, analyzed data and helped prepare the manuscript; J.A.H. and D.M.S.-K. performed biochemical assays and analyzed data; L.T. performed DFT calculation studies and analyzed data; K.N.R. analyzed gene expression profiling data; J.L., W.R.-B. and B.Z. performed gene expression analysis and analyzed data; H.W. and C.S. designed experimental set-up for relaxation experiments, performed relaxation experiments and analyzed data.
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Competing interests
R.M. has financial interests in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals, and is the inventor on IP licensed to these two entities. S.J.H. has financial interests in Rodin Therapeutics and is an inventor on IP licensed to this entity. None of these entities were involved in the present study and the licensed IP does not include any of the work presented here. R.M., B.G., J.A.H., S.A.R. and S.J.H. have filed a patent application on the reported invention (WO 2014160221).
Supplementary information
Supplementary Text and Figures
Supplementary Results and Supplementary Figures 1–16. (PDF 28097 kb)
Supplementary Data Set
Gene expression SNR scores; BG14, CI-994, and C60 response gene IDs (XLSX 301 kb)
Supplementary Note
Supplementary Note 1 (PDF 791 kb)
LED array
Video shows footprint of LED array in an incubator and exposure of 470 nm light (8.5 mW/cm2) modulating at 1 Hz (1 s on/7 s off) per row both with and without a 96-well plate. (MOV 21364 kb)
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Reis, S., Ghosh, B., Hendricks, J. et al. Light-controlled modulation of gene expression by chemical optoepigenetic probes. Nat Chem Biol 12, 317–323 (2016). https://doi.org/10.1038/nchembio.2042
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DOI: https://doi.org/10.1038/nchembio.2042
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