@Article{ecn.2013.0336,
AUTHOR = {Thomas Werner, Susan M. Dombrowski, Carlos Zgheib, Fouad A. Zouein, Henry L. Keen, Mazen Kurdi, George W. Booz},
TITLE = {Elucidating functional context within microarray data by integrated transcription factor-focused gene-interaction and regulatory network analysis},
JOURNAL = {European Cytokine Network},
VOLUME = {24},
YEAR = {2013},
NUMBER = {2},
PAGES = {75--90},
URL = {http://www.techscience.com/ECN/v24n2/65632},
ISSN = {1952-4005},
ABSTRACT = {Microarrays do not yield direct evidence for functional connections between genes. However, transcription
factors (TFs) and their binding sites (TFBSs) in promoters are important for inducing and coordinating
changes in RNA levels, and thus represent the first layer of functional interaction. Similar to genes, TFs act only in
context, which is why a TF/TFBS-based promoter analysis of genes needs to be done in the form of gene(TF)-gene
networks, not individual TFs or TFBSs. In addition, integration of the literature and various databases (e.g. GO,
MeSH, etc) allows the adding of genes relevant for the functional context of the data even if they were initially missed
by the microarray as their RNA levels did not change significantly. Here, we outline a TF-TFBSs network-based
strategy to assess the involvement of transcription factors in agonist signaling and demonstrate its utility in deciphering
the response of human microvascular endothelial cells (HMEC-1) to leukemia inhibitory factor (LIF). Our
strategy identified a central core of eight TFs, of which only STAT3 had previously been definitively linked to LIF in
endothelial cells. We also found potential molecular mechanisms of gene regulation in HMEC-1 upon stimulation
with LIF that allow for the prediction of changes of genes not used in the analysis. Our approach, which is readily
applicable to a wide variety of expression microarray and next generation sequencing RNA-seq results, illustrates
the power of a TF-gene networking approach for elucidation of the underlying biology.},
DOI = {10.1684/ecn.2013.0336}
}