PubMed · 12914689
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Jeffrey M Rosen. 2003-08-08. Striking it rich by data mining.. https://doi.org/10.1016/s0092-8674(03)00601-9
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In human immunodeficiency virus type 1 (HIV-1) latently infected cells, NF-kappaB (NF-kappaB) plays a critical role in the transcriptional induction of the HIV-1 promoter. The trans-activating ability of NF-kappaB can be modified by another nuclear factor C/EBPbeta that can physically bind to NF-kappaB and regulate its activity. Because the HIV-1 promoter also contains a C/EBPbeta site adjacent to the NF-kappaB site, the present study examined cooperative functional in vivo interaction of the p65 subunit of NF-kappaB and C/EBPbeta, and the impact of Tat in this event. We demonstrated that ectopic expression of p65 along with Tat increases p65 binding to HIV-1 LTR, and that this increase correlates with enhanced HIV-1 promoter activity. Further, co-expression of C/EBPbeta and Tat leads to a decrease in p65 binding, which allows C/EBPbeta to bind more efficiently to the LTR. Inhibition of p65 expression by siRNA significantly decreases C/EBPbeta-binding and LTR expression. Using ChIP assay, we confirmed the existence of an interchange between p65 and C/EBPbeta and their abilities to bind to the LTR in vivo. These observations demonstrate that a delicate balance of interaction between p65, C/EBPbeta, and Tat can dictate the level of HIV-1 LTR transcription.
We present a Bayesian hierarchical model and Gibbs Sampling implementation that integrates gene expression, ChIP binding, and transcription factor motif data in a principled and robust fashion. COGRIM was applied to both unicellular and mammalian organisms under different scenarios of available data. In these applications, we demonstrate the ability to predict gene-transcription factor interactions with reduced numbers of false-positive findings and to make predictions beyond what is obtained when single types of data are considered.
TNF is a major mediator of inflammation, immunity, and apoptosis. Pre-exposure to TNF reduces sensitivity to restimulation, a phenomenon known as tolerance, considered as protective in sepsis, but also as a paradigm for immunoparalysis. Earlier experiments in TNF-tolerant cells display inhibition of NF-kappaB-dependent IL-8 gene expression at the transcriptional level with potential involvement of C/EBPbeta. In this study, we have shown that a kappaB motive was sufficient to mediate transcriptional inhibition under TNF tolerance conditions in monocytic cells. Furthermore, in tolerant cells, TNF-induced NF-kappaB p65 phosphorylation was markedly decreased, which was accompanied by the formation of C/EBPbeta-p65 complexes. Remarkably, in C/EBPbeta(-/-) cells incubated under the conditions of TNF tolerance, neither impairment of transcription nor inhibition of p65 phosphorylation was observed. Finally, we showed that C/EBPbeta overexpression reduced p65-mediated transactivation and that association of C/EBPbeta with p65 specifically prevented p65 phosphorylation. Our data demonstrate that C/EBPbeta is an essential signaling component for inhibition of NF-kappaB-mediated transcription in TNF-tolerant cells and suggest that this is caused by blockade of p65 phosphorylation. These results define a new molecular mechanism responsible for TNF tolerance in monocytic cells that may contribute to the unresponsiveness seen in patients with sepsis.