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Modulation of NF-?B-dependent gene transcription using programmable DNA minor groove binders.


ABSTRACT: Nuclear factor ?B (NF-?B) 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 ?B sites and reducing the expression of various NF-?B-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-?B inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-?-inducible genes. Inhibition of NF-?B DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists.

SUBMITTER: Raskatov JA 

PROVIDER: S-EPMC3268328 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Raskatov Jevgenij A JA   Meier Jordan L JL   Puckett James W JW   Yang Fei F   Ramakrishnan Parameswaran P   Dervan Peter B PB  

Proceedings of the National Academy of Sciences of the United States of America 20111227 4


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 wi  ...[more]

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