Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics.
Stephen A. Ramsey,Sandy L. Klemm,Daniel E. Zak,Kathleen A. Kennedy,Vesteinn Thorsson,Bin Li,Mark Gilchrist,Elizabeth S. Gold,Carrie D. Johnson,Vladimir Litvak,Garnet Navarro,Jared C. Roach,Carrie M. Rosenberger,Alistair G. Rust,Natalya Yudkovsky,Alan Aderem,Ilya Shmulevich +16 more
TLDR
A novel regulator (TGIF1) that may have a role in macrophage activation was identified and a novel statistical test was developed to assess the significance of the time-lagged correlation.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.read more
Citations
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Inflammatory links between obesity and metabolic disease.
Carey N. Lumeng,Alan R. Saltiel +1 more
TL;DR: This Review highlights the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation and underscores how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses.
Journal ArticleDOI
Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation
Jia Xue,Susanne Schmidt,Jil Sander,Astrid M. Draffehn,Wolfgang Krebs,Inga Quester,Dominic De Nardo,Trupti D. Gohel,Martina Emde,Lisa Schmidleithner,Hariharasudan Ganesan,Andrea Niño-Castro,Michael R. Mallmann,Larisa I. Labzin,Heidi Theis,Michael Kraut,Marc Beyer,Eicke Latz,Eicke Latz,Tom C. Freeman,Thomas Ulas,Joachim L. Schultze +21 more
TL;DR: By integrating murine data from the ImmGen project, this work proposes a refined, activation-independent core signature for human and murine macrophages that serves as a framework for future research into regulation of macrophage activation in health and disease.
Journal ArticleDOI
Transcriptional control of the inflammatory response
Ruslan Medzhitov,Tiffany Horng +1 more
TL;DR: The mechanisms of and the emerging principles in the transcriptional regulation of inflammatory responses in diverse physiological settings are discussed.
Journal ArticleDOI
Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells
Michal Rabani,Joshua Z. Levin,Lin Fan,Xian Adiconis,Raktima Raychowdhury,Manuel Garber,Andreas Gnirke,Chad Nusbaum,Nir Hacohen,Nir Friedman,Ido Amit,Aviv Regev,Aviv Regev +12 more
TL;DR: This study combines metabolic labeling of RNA at high temporal resolution with advanced RNA quantification and computational modeling to estimate RNA transcription and degradation rates during the response of mouse dendritic cells to lipopolysaccharide.
Journal ArticleDOI
Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses.
Ido Amit,Manuel Garber,Nicolas Chevrier,Ana Paula Leite,Ana Paula Leite,Yoni Donner,Thomas Eisenhaure,Mitchell Guttman,Mitchell Guttman,Jennifer K. Grenier,Weibo Li,Or Zuk,Lisa A. Schubert,Brian Birditt,Tal Shay,Alon Goren,Alon Goren,Xiaolan Zhang,Zachary D. Smith,Raquel P. Deering,Rebecca C. McDonald,Moran N. Cabili,Bradley E. Bernstein,Bradley E. Bernstein,John L. Rinn,Alexander Meissner,David E. Root,Nir Hacohen,Nir Hacohen,Aviv Regev,Aviv Regev,Aviv Regev +31 more
TL;DR: This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.
References
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