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Light-controlled modulation of gene expression by chemical optoepigenetic probes

Nature Chemical Biology volume 12, pages 317–323 (2016)Cite this article

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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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Figure 1: Overview of photochromic HDAC inhibitor design for use in COMET.
Figure 2: Optical properties and validation of light-dependent inhibitory activity toward recombinant HDACs of COMET probes.
Figure 3: Light-dependent control of the human epigenome with COMET probes.
Figure 4: Light-dependent spatial control of epigenetic regulation with the COMET probe BG14.
Figure 5: Characterization of COMET-mediated gene expression signatures in human cells.

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References

  1. Haggarty, S.J. & Tsai, L.H. Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. Neurobiol. Learn. Mem. 96, 41–52 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Orozco-Solis, R. & Sassone-Corsi, P. Epigenetic control and the circadian clock: linking metabolism to neuronal responses. Neuroscience 264, 76–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Goldberg, A.D., Allis, C.D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Arrowsmith, C.H., Bountra, C., Fish, P.V., Lee, K. & Schapira, M. Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Knight, Z.A. & Shokat, K.M. Chemical genetics: where genetics and pharmacology meet. Cell 128, 425–430 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Stockwell, B.R. Exploring biology with small organic molecules. Nature 432, 846–854 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fenno, L., Yizhar, O. & Deisseroth, K. The development and application of optogenetics. Annu. Rev. Neurosci. 34, 389–412 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472–476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beharry, A.A. & Woolley, G.A. Azobenzene photoswitches for biomolecules. Chem. Soc. Rev. 40, 4422–4437 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Fehrentz, T., Schönberger, M. & Trauner, D. Optochemical genetics. Angew. Chem. Int. Edn Engl. 50, 12156–12182 (2011).

    Article  CAS  Google Scholar 

  12. Kramer, R.H., Mourot, A. & Adesnik, H. Optogenetic pharmacology for control of native neuronal signaling proteins. Nat. Neurosci. 16, 816–823 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schönberger, M., Althaus, M., Fronius, M., Clauss, W. & Trauner, D. Controlling epithelial sodium channels with light using photoswitchable amilorides. Nat. Chem. 6, 712–719 (2014).

    Article  PubMed  Google Scholar 

  14. Frank, J.A. et al. Photoswitchable fatty acids enable optical control of TRPV1. Nat. Commun. 6, 7118 (2015).

    Article  PubMed  Google Scholar 

  15. Brieke, C., Rohrbach, F., Gottschalk, A., Mayer, G. & Heckel, A. Light-controlled tools. Angew. Chem. Int. Edn Engl. 51, 8446–8476 (2012).

    Article  CAS  Google Scholar 

  16. Copeland, R.A., Pompliano, D.L. & Meek, T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov. 5, 730–739 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Niino, H. et al. Stabilization of a labile cis-azobenzene derivative with amphiphilic cyclodextrins. Chem. Lett. 17, 1227–1230 (1988).

    Article  Google Scholar 

  18. Shinkai, S., Minami, T., Kusano, Y. & Manabe, O. Photoresponsive crown ethers. 8. Azobenzenophane-type switched-on crown ethers which exhibit an all-or-nothing change in ion-binding ability. J. Am. Chem. Soc. 105, 1851–1856 (1983).

    Article  CAS  Google Scholar 

  19. Bressi, J.C. et al. Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg. Med. Chem. Lett. 20, 3142–3145 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Bradner, J.E. et al. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238–243 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bantscheff, M. et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255–265 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Andrews, D.M. et al. Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 18, 2580–2584 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Lauffer, B.E. et al. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J. Biol. Chem. 288, 26926–26943 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garcia-Amorós, J., Martínez, M., Finkelmann, H. & Velasco, D. Kinetico-mechanistic study of the thermal cis-to-trans isomerization of 4,4′-dialkoxyazoderivatives in nematic liquid crystals. J. Phys. Chem. B 114, 1287–1293 (2010).

    Article  PubMed  Google Scholar 

  25. Zheng, Y., Thomas, P.M. & Kelleher, N.L. Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites. Nat. Commun. 4, 2203 (2013).

    Article  PubMed  Google Scholar 

  26. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Montojo, J. et al. GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. Bioinformatics 26, 2927–2928 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Beckers, T. et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int. J. Cancer 121, 1138–1148 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Gräff, J. & Tsai, L.H. The potential of HDAC inhibitors as cognitive enhancers. Annu. Rev. Pharmacol. Toxicol. 53, 311–330 (2013).

    Article  PubMed  Google Scholar 

  30. Gräff, J. et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483, 222–226 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schroeder, F.A. et al. A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. PLoS One 8, e71323 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gräff, J. et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156, 261–276 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bolden, J.E., Peart, M.J. & Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Peters, J.U. Polypharmacology - foe or friend? J. Med. Chem. 56, 8955–8971 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Banks, J.L. et al. Integrated Modeling Program, Applied Chemical Theory (IMPACT). J. Comput. Chem. 26, 1752–1780 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee, C., Yang, W. & Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter 37, 785–789 (1988).

    Article  CAS  PubMed  Google Scholar 

  37. Marenich, A.V., Cramer, C.J. & Truhlar, D.G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 113, 6378–6396 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Chirlian, L.E. & Francl, M.M. Atomic charges derived from electrostatic potentials: a detailed study. J. Comput. Chem. 8, 894–905 (1987).

    Article  CAS  Google Scholar 

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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.

Author information

Author notes

  1. Balaram Ghosh

    Present address: Present address: Department of Pharmacy, BITS-Pilani at Hyderabad Campus, Hyderabad, India.,

  2. Surya A Reis and Balaram Ghosh: These authors contributed equally to this work.

Authors and Affiliations

  1. Chemical Neurobiology Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA

    Surya A Reis, Balaram Ghosh & Stephen J Haggarty

  2. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Surya A Reis, Balaram Ghosh & Stephen J Haggarty

  3. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA

    Surya A Reis, Balaram Ghosh & Stephen J Haggarty

  4. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Balaram Ghosh, J Adam Hendricks, D Miklos Szantai-Kis, Lisa Törk & Ralph Mazitschek

  5. Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Kenneth N Ross

  6. Genometry Inc., Cambridge, Massachusetts, USA

    Justin Lamb, Willis Read-Button & Baixue Zheng

  7. Department of Electrical & Computer Engineering, University of Massachusetts, Amherst, Massachusetts, USA

    Hongtao Wang & Christopher Salthouse

  8. Center for Personalized Health Monitoring, University of Massachusetts, Amherst, Massachusetts, USA

    Hongtao Wang & Christopher Salthouse

  9. Broad Institute of Harvard & Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Stephen J Haggarty & Ralph Mazitschek

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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.

Corresponding authors

Correspondence to Stephen J Haggarty or Ralph Mazitschek.

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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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