Systems-Level Analysis of Innate Immunity

Zak, Daniel E.; Tam, Vincent C.; Aderem, Alan

doi:10.1146/annurev-immunol-032713-120254

Cited by 45 publications

(41 citation statements)

References 160 publications

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“…4E; Supplemental File S2), such as RFX5, SMAD1, and EOMES. The rapid evolution of immune response genes and TFs is supported by many studies in vertebrates and in Drosophila melanogaster, demonstrating that while the central machinery of immune responses is strongly conserved, components of the extended molecular networks can evolve rapidly or diversify as a consequence of evolutionary competition between hosts and pathogens (Jansa et al 2003;Vallender and Lahn 2004;Sackton et al 2007;Obbard et al 2009;Schadt 2009;Grueber et al 2014;Lazzaro and Schneider 2014;Salazar-Jaramillo et al 2014;Zak et al 2014;Sironi et al 2015;Wertheim 2015). Ape-specific CREs are enriched for binding sites of TFs involved in liver function but also in brain and neural system proliferation and development (Fig.…”

Section: Specific Transcription Factor Motifs Are Associated With Regmentioning

confidence: 94%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNAseq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

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Section: Specific Transcription Factor Motifs Are Associated With Regmentioning

confidence: 94%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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“…In infectious disease, analysis of gene expression profiles has provided an understanding of host immune responses with the potential to improve diagnosis, develop vaccines, and design new therapies (1)(2)(3). Leprosy offers an attractive model for investigating immune pathways of host defense and disease pathogenesis (4), as the disease forms a spectrum in which clinical manifestations correlate with the type of immune response.…”

Section: Introductionmentioning

confidence: 99%

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

Inkeles¹,

Teles²,

Pouldar³

et al. 2016

JCI Insight

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“…They fail to account for the complexities and redundancies that arise from cytokine interactions inherent to the immune reaction. 3,4 In addition to examining individual cytokines, investigating associations between them can lead to a better understanding of the inflammatory process after aSAH. A systematic approach based on network theory can offer insights into the multifactorial relationships and can delineate the complexities underlying inflammatory processes.…”

mentioning

confidence: 99%

Systematic model of peripheral inflammation after subarachnoid hemorrhage

Savarraj¹,

Parsha²,

Hergenroeder³

et al. 2017

Neurology

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Objective: To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.Methods: This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: ,24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously.Results: Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-a (TNF-a) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a plateletderived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-a, compared to those with lower clinical severity. Conclusions:Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH. Neurology ® 2017;88:1535-1545 GLOSSARY aSAH 5 aneurysmal subarachnoid hemorrhage; CSF 5 colony-stimulating factor; DCI 5 delayed cerebral ischemia; EGF 5 epidermal growth factor; FGF-2 5 fibroblast growth factor-2; FLT3L 5 FMS-like tyrosine kinase 3 ligand; HH 5 Hunt-Hess; IFN-a2 5 interferon-a2; IFNG 5 type-II interferon family; IL 5 interleukin; MIP 5 macrophage inflammatory protein; Pcc 5 Pearson correlation coefficient; PDGF 5 platelet-derived growth factor; sCD40L 5 soluble CD40 ligand; SI 5 similarity index; TNF 5 tumor necrosis factor; VEGF 5 vascular endothelial growth factor.Aneurysmal subarachnoid hemorrhage (aSAH) affects z30,000 people annually and accounts for 10% to 15% of all strokes.1 Despite improvements in clinical management, morbidity after aSAH remains high. Studies have shown that early elevation of central and peripheral inflammatory cytokines is associated with delayed neurologic deteriorations.2 However, such studies typically use methods to examine differences in concentrations of individual cytokines across disease severity or clinical outcomes. They fail to account for the complexities an...

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Systems-Level Analysis of Innate Immunity

Cited by 45 publications

References 160 publications

Transposable elements are the primary source of novelty in primate gene regulation

Transposable elements are the primary source of novelty in primate gene regulation

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

Systematic model of peripheral inflammation after subarachnoid hemorrhage

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