Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics.
Macrophages are versatile immune cells that can detect a variety of pathogen-associated molecular patterns through their Toll-like receptors (TLRs). In response to microbial challenge, the TLR-stimulated macrophage undergoes an activation program controlled by a dynamically inducible transcriptional regulatory network. Mapping a complex mammalian transcriptional network poses significant challenges and requires the integration of multiple experimental data types. In this work, we inferred a transcriptional network underlying TLR-stimulated murine macrophage activation. Microarray-based expression profiling and transcription factor binding site motif scanning were used to infer a network of associations between transcription factor genes and clusters of co-expressed target genes. The time-lagged correlation was used to analyze temporal expression data in order to identify potential causal influences in the network. A novel statistical test was developed to assess the significance of the time-lagged correlation. Several associations in the resulting inferred network were validated using targeted ChIP-on-chip experiments. The network incorporates known regulators and gives insight into the transcriptional control of macrophage activation. Our analysis identified a novel regulator (TGIF1) that may have a role in macrophage activation.
Ramsey
Stephen A
SA
Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org
Klemm
Sandy L
SL
Zak
Daniel E
DE
Kennedy
Kathleen A
KA
Thorsson
Vesteinn
V
Li
Bin
B
Gilchrist
Mark
M
Gold
Elizabeth S
ES
Johnson
Carrie D
CD
Litvak
Vladimir
V
Navarro
Garnet
G
Roach
Jared C
JC
Rosenberger
Carrie M
CM
Rust
Alistair G
AG
Yudkovsky
Natalya
N
Aderem
Alan
A
Shmulevich
Ilya
I
D020816:Amino Acid Motifs; D000818:Animals; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D018511:Systems Integration; D051193:Toll-Like Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
D051193:Toll-Like Receptors; D014157:Transcription Factors