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

Author:
Raskatov, Jevgenij A., Meier, Jordan L., Puckett, James W., Yang, Fei, Ramakrishnan, Parameswaran, Dervan, Peter B.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.4 pp. 1023-1028
ISSN:
0027-8424
Subject:
DNA, antagonists, cell death, chromatin, genes, immune response, interleukin-6, interleukin-8, reverse transcriptase polymerase chain reaction, transcription (genetics), transcription factors
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.
Agid:
439322