Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders.
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.
Division of Chemistry and Chemical Engineering and Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Jevgenij A
JA
Raskatov
Jordan L
JL
Meier
James W
JW
Puckett
Fei
F
Yang
Parameswaran
P
Ramakrishnan
Peter B
PB
Dervan
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009691:Nucleic Acid Denaturation; D009757:Nylons / Q000378:metabolism* / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011725:Pyridines; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*
D006575:Heterocyclic Compounds, 3-Ring; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D009757:Nylons; C456319:PS1145; D017395:Plasminogen Activator Inhibitor 1; D011725:Pyridines; C051321:SERPINE1 protein, human; D004247:DNA