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

Raskatov, Jevgenij A., Meier, Jordan L., Puckett, James W., Yang, Fei, Ramakrishnan, Parameswaran, Dervan, Peter B.
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.4 pp. 1023-1028
DNA, antagonists, cell death, chromatin, genes, immune response, interleukin-6, interleukin-8, reverse transcriptase polymerase chain reaction, transcription (genetics), transcription factors
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.