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ChIP-seq of transcription factors regulating the TLR-induced transcriptional cascades in macrophages

ABSTRACT: Toll-like receptors (TLRs) are responsible for sensing pathogen components, initiating cascades of signaling pathways, transcription factors, chromatin regulators, and activating thousands of genes contributing to diverse immune functions in macrophages. Conventional system approaches have been used to analyze TLR-induced transcriptional cascades. However, commonly used approaches possess a number of limitations, including a bias toward weakly induced genes, which are far more prevalent than strongly induced genes, and an inability to distinguish functionally important protein-DNA interactions identified by ChIP-seq from interactions that may be functionally insignificant. To develop a better understanding of a TLR-induced transcriptional cascade, we used more stringent criteria to analyze RNA-seq, ChIP-seq, and transcription factor binding motif data sets. Our analysis provided a number of insights into the regulation of an inducible transcriptional cascade. This stringent and quantitative strategy can effectively reveal gene-specific regulatory mechanisms from genome-wide studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE99895 | GEO | 2017/06/11

SECONDARY ACCESSION(S): PRJNA389971

REPOSITORIES: GEO

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Project description:Macrophages provide an interface between innate and adaptive immunity and are important long-lived reservoirs for Human Immunodeficiency Virus Type-1 (HIV-1). Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection. To evaluate complex interrelated processes and to assemble an integrated view of activated signaling networks, a systems biology strategy was applied to genomic and proteomic responses by primary human macrophages over the course of HIV-1 infection. Macrophage responses, including cell cycle, calcium, apoptosis, mitogen-activated protein kinases (MAPK), and cytokines/chemokines, to HIV-1 were temporally regulated, in the absence of cell proliferation. In contrast, Toll-like receptor (TLR) pathways remained unaltered by HIV-1, although TLRs 3, 4, 7, and 8 were expressed and responded to ligand stimulation in macrophages. HIV-1 failed to activate phosphorylation of IRAK-1 or IRF-3, modulate intracellular protein levels of Mx1, an interferon-stimulated gene, or stimulate secretion of TNF, IL-1b, or IL-6. Activation of pathways other than TLR was inadequate to stimulate, via cross-talk mechanisms through molecular hubs, the production of proinflammatory cytokines typical of a TLR response. HIV-1 sensitized macrophage responses to TLR ligands, and the magnitude of viral priming was related to virus replication. HIV-1 induced a primed, proinflammatory state, M1HIV, which increased the responsiveness of macrophages to TLR ligands. HIV-1 might passively evade pattern recognition, actively inhibit or suppress recognition and signaling, or require dynamic interactions between macrophages and other cells, such as lymphocytes or endothelial cells. HIV-1 evasion of TLR recognition and simultaneous priming of macrophages may represent a strategy for viral survival, contribute to immune pathogenesis, and provide important targets for therapeutic approaches. Affymetrix arrays were used to identify genomic macrophage response to HIV during viral spread in culture. Experiment Overall Design: An HIV-1 spreading infection was established in primary human macrophages. RNA was extracted from both viral- and mock-infected macrophages cultures over 7 days and hybridized to Affymetrix HG-U95Av2 GeneChips for analysis.

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ChIP-seq of transcription factors regulating the TLR-induced transcriptional cascades in macrophages

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