Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders
Open Access
- 27 December 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (4), 1023-1028
- https://doi.org/10.1073/pnas.1118506109
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.Keywords
This publication has 37 references indexed in Scilit:
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010
- Immunity, Inflammation, and CancerCell, 2010
- Allosteric modulation of DNA by small moleculesProceedings of the National Academy of Sciences of the United States of America, 2009
- SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life SpanCell, 2009
- Modulating Hypoxia-Inducible Transcription by Disrupting the HIF-1–DNA InterfaceACS Chemical Biology, 2007
- Completion of a programmable DNA-binding small molecule libraryTetrahedron, 2007
- Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamideProceedings of the National Academy of Sciences of the United States of America, 2007
- Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibitionBioorganic & Medicinal Chemistry, 2007
- Inhibitors of NF-κB signaling: 785 and countingOncogene, 2006
- NF-κB in cancer: from innocent bystander to major culpritNature Reviews Cancer, 2002