title: Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics.
abstract: 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.
authors: Institute for Systems Biology, Seattle, Washington, United States of America. sramsey@systemsbiology.org
authors: Stephen A
authors: SA
authors: Ramsey
authors: Sandy L
authors: SL
authors: Klemm
authors: Daniel E
authors: DE
authors: Zak
authors: Kathleen A
authors: KA
authors: Kennedy
authors: Vesteinn
authors: V
authors: Thorsson
authors: Bin
authors: B
authors: Li
authors: Mark
authors: M
authors: Gilchrist
authors: Elizabeth S
authors: ES
authors: Gold
authors: Carrie D
authors: CD
authors: Johnson
authors: Vladimir
authors: V
authors: Litvak
authors: Garnet
authors: G
authors: Navarro
authors: Jared C
authors: JC
authors: Roach
authors: Carrie M
authors: CM
authors: Rosenberger
authors: Alistair G
authors: AG
authors: Rust
authors: Natalya
authors: N
authors: Yudkovsky
authors: Alan
authors: A
authors: Aderem
authors: Ilya
authors: I
authors: Shmulevich
mesh_terms: 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*
chemical_list: D051193:Toll-Like Receptors; D014157:Transcription Factors