A dynamic network of transcription in LPS-treated human subjects.
BACKGROUND
Understanding the transcriptional regulatory networks that map out the coordinated dynamic responses of signaling proteins, transcription factors and target genes over time would represent a significant advance in the application of genome wide expression analysis. The primary challenge is monitoring transcription factor activities over time, which is not yet available at the large scale. Instead, there have been several developments to estimate activities computationally. For example, Network Component Analysis (NCA) is an approach that can predict transcription factor activities over time as well as the relative regulatory influence of factors on each target gene.


RESULTS
In this study, we analyzed a gene expression data set in blood leukocytes from human subjects administered with lipopolysaccharide (LPS), a prototypical inflammatory challenge, in the context of a reconstructed regulatory network including 10 transcription factors, 99 target genes and 149 regulatory interactions. We found that the computationally estimated activities were well correlated to their coordinated action. Furthermore, we found that clustering the genes in the context of regulatory influences greatly facilitated interpretation of the expression data, as clusters of gene expression corresponded to the activity of specific factors or more interestingly, factor combinations which suggest coordinated regulation of gene expression. The resulting clusters were therefore more biologically meaningful, and also led to identification of additional genes under the same regulation.


CONCLUSIONS
Using NCA, we were able to build a network that accounted for between 8-11% genes in the known transcriptional response to LPS in humans. The dynamic network illustrated changes of transcription factor activities and gene expressions as well as interactions of signaling proteins, transcription factors and target genes.
Seok
Junhee
J
Department of Bioengineering, Stanford University, Stanford, California, USA. jseok@stanford.edu
Xiao
Wenzhong
W
Moldawer
Lyle L
LL
Davis
Ronald W
RW
Covert
Markus W
MW
D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D049490:Systems Biology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D008070:Lipopolysaccharides; D014157:Transcription Factors