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Published January 24, 2012 | Published + Supplemental Material
Journal Article Open

Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Abstract

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5′-WGGWWW-3′ and 5′GGGWWW-3′. The compound is capable of binding to κB sites and reducing the expression of various NF-κB–driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α–inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists.

Additional Information

© 2012 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Peter B. Dervan, November 10, 2011 (sent for review September 14, 2011). Prof. David Baltimore, Dr. Chee-Kwee Ea, and Dr. John W. Phillips are gratefully acknowledged for helpful discussions. J.A.R. is grateful to the Alexander von Humboldt Foundation for the award of a Feodor Lynen postdoctoral fellowship. J.L.M. acknowledges the American Cancer Society for a postdoctoral fellowship (PF-10-015-01-CDD). Sequencing was conducted at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. This work was supported by The Ellison Medical Foundation (Grant AG-SS-2256-09). Author contributions: J.A.R. and P.B.D. designed research; J.A.R., J.L.M., and P.R. performed research; J.W.P. and F.Y. contributed new reagents/analytic tools; J.A.R., J.L.M., J.W.P., and P.R. analyzed data; and J.A.R. and P.B.D. wrote the paper. The authors declare no conflict of interest. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE34329). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1118506109/-/DCSupplemental.

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Published - Raskatov2012p17248P_Natl_Acad_Sci_Usa.pdf

Supplemental Material - pnas.1118506109_SI.pdf

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