Expression-based monitoring of transcription factor activity: the TELiS database

Abstract

In two validation studies, TELiS accurately detected in vivo activation of NF-kappaB and the Type I interferon system by HIV-1 infection and pharmacologic activation of the glucocorticoid receptor in peripheral blood mononuclear cells. The population-based statistical inference underlying TELiS out-performed conventional statistical tests in analytic sensitivity, with parametric studies demonstrating accurate identification of transcription factor activity from as few as 20 differentially expressed genes. TELiS thus provides a simple, rapid and sensitive tool for identifying transcription control pathways mediating observed gene expression dynamics.

A Functional Genomic Fingerprint of Chronic Stress in Humans: Blunted Glucocorticoid and Increased NF-κB Signaling

“…TELiS analyzes differential gene expression data in terms of the prevalence of transcription factorbinding motifs (TFBMs) within the promoters of differentially expressed genes. This approach can accurately identify the activation of specific hormone or cytokine signaling pathways based on the resulting pattern of gene induction which occurs selectively in genes bearing TFBMs responsive to transcription factors activated through that pathway (23). The present analyses assessed glucocorticoid receptor activity using the TRANSFAC V$GR_Q6 DNA motif, and NF-κB/Rel transcription factor activity using the V$CREL_01 motif (which was characterized by binding of the p50/p65 cRel heterodimer, but can also bind RelB and other NF-κB/Rel family proteins; 33).…”

Depression, social support, and beta-adrenergic transcription control in human ovarian cancer

“…Total RNA was extracted and treated with RNAse-free DNAse (Qiagen) following the manufacturer's protocol (supplemented by one additional wash in RW1 reagent and one additional wash in RPE reagent to remove excess salt). RNA purity and integrity were assessed using an Agilent 2100 bioanalyzer (Agilent Technologies, Santa Clara CA), and genome-wide transcription profiling was carried out using Affymetrix U133A high density oligonucleotide arrays (Affymetrix, Santa Clara CA) in the UCLA DNA Microarray Core, as previously described (Cole, Galic et al 2003;Cole, Yan et al 2005). Low level gene expression was quantified by Robust Multiarray Averaging (Bolstad, Irizarry et al 2003), and differentially expressed genes were identified by a ≥ 2-fold difference in mean expression level (corresponding to a 5% False Discovery Rate) (Benjamini and Hochberg 1995;Cole, Galic et al 2003) in paired comparisons of grade-and stage-matched pairs of tumors from high vs. low biobehavioral risk patients.…”

“…The primary hypothesis regarding CREB/ATF transcription factors and secondary hypotheses regarding NF-κB/Rel and Ets family transcription factors were tested using a 2-sample variant of the Transcription Element Listening System (TELiS) (Cole 2005;Cole, Yan et al 2005). TELiS contains data on the prevalence of 192 vertebrate transcription factor-binding motifs (TFBMs) from the TRANSFAC database (Wingender, Dietze et al 1996) in the promoters of all genes assayed by the Affymetrix U133A high-density oligonucleotide array.…”

“…TELiS contains data on the prevalence of 192 vertebrate transcription factor-binding motifs (TFBMs) from the TRANSFAC database (Wingender, Dietze et al 1996) in the promoters of all genes assayed by the Affymetrix U133A high-density oligonucleotide array. TELiS differential expression analyses monitor the functional activity of the transcription factors binding to each TFBM by defining putative transcription factor-responsive genes (TFRGs) a priori based on promoter DNA sequence information, and then testing for empirical differential expression of those TFRGs using established statistical approaches (Cole, Yan et al 2005). In the present study, activation of the CREB/ATF transcription control pathway was assessed by genes bearing the V$CREBP1_Q2 motif, activation of the NF-κB/Rel factors cRel and RelA were assessed by V$CREL_01 and V$NFKAPPAB65_01 motifs, activation of STAT family transcription factors was assessed by V$STAT_01, and activation of the prototypic Ets family transcription factor ELK1 was assessed by V$ELK1_01.…”

“…betaadrenergic signaling can enhance the expression of both IL6 and VEGFA genes in model systems (Lutgendorf, Cole et al 2003;Thaker, Han et al 2006;Nilsson, Armaiz-Pena et al 2007). To determine whether beta-adrenergic regulation of gene expression also occurs in primary ovarian cancer, we profiled genome-wide transcriptional profiles in tumor tissues from patients with high biobehavioral risk profiles (high depressive symptoms and low social support) vs. low risk profiles (low depression and high social support), and used a hypothesistesting bioinformatic strategy to assess CREB/ATF transcriptional signaling (Cole, Yan et al 2005). We also tested secondary hypotheses that other transcription control pathways known to be activated by beta-adrenergic signaling, such as NF-κB/Rel, STAT, and Ets transcription factors, might also show increased activity in tumors from patients with high biobehavioral risk profiles.…”