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Title: Temporal regulatory interactions of lipid metabolism and inflammation in defining macrophage inflammatory phenotype      
keywords:
Other
ID:
PRJNA315821
description:
Systematic analyses of the temporal dynamics of transcriptomes and chromatin landscapes of macrophages during timecourse of TLR4-mediated inflammatory response. As a multifunctional effector cell, macrophages play pivotal roles in both the induction and resolution components of varied inflammatory processes. During the course of an inflammation response, macrophages engage in a homeostatic program characterized by tightly coordinated modulation of temporal outputs of both lipid metabolism and inflammation. We demonstrate inversely biphasic temporal dynamics of specific fatty acid metabolic and inflammatory gene expression profiles, associated with concordant temporal reprogramming of macrophage fatty acid profiles. In part, the late phase of the macrophage inflammatory response is characterized by tailoring of fatty acid related gene expressions, facilitating both significant induction of anti-inflammatory unsaturated fatty acid production and associated resolution of inflammation. We demonstrate the biphasic temporal dynamics of macrophage inflammation, specifically anti-inflammatory omega-3 and omega-9 unsaturated fatty acid levels, are transcriptionally driven genome-wide by an unexpected shift from an LXR to SREBP1-dominant regulatory program in the late phase inflammatory response. Collectively, our findings reveal a novel Srebp1-driven mechanism allowing the intimate inverse temporal relationship between the transcriptional regulation of inflammatory and fatty acid metabolic outputs; whereby modulation key transcriptional regulators (LXR, SREBP1 and NF-kB) of these pathways coordinate appropriate temporal tailoring of local enhancer associated reprogramming and eventual pathway regulatory interactions, during the course of TLR4-dependent inflammatory response in macrophages. This specific Srebp-driven, temporal reprogramming of macrophage fatty acid metabolism, characterized by late phase induction of anti-inflammatory unsaturated fatty acid production, is necessary for appropriate resolution of inflammation. Thus, this study suggests that selective reprogramming of macrophage lipid metabolism can serve as a viable therapeutic intervention aimed at ameliorating chronic inflammation and varied metabolic syndrome associated states. Overall design: Chromatin mark H3K27Ac, H3K4me2 and transcription factors SREBP1, LXR, p65, PU.1 and RNA polymerase2 were assessed by ChIP-Seq and RNA-Seq were used to measure gene expression in the timepoints after inflammatory stimuli
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA315821
authentication:
none
authorization:
none
ID:
pmid:28041958
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • P01 DK074868/DK/NIDDK NIH HHS/United States

  • R01 CA173903/CA/NCI NIH HHS/United States

  • R01 DK091183/DK/NIDDK NIH HHS/United States

  • P30 DK063491/DK/NIDDK NIH HHS/United States

  • R21 HL088083/HL/NHLBI NIH HHS/United States

  • T32 GM007198/GM/NIGMS NIH HHS/United States

  • P30 CA014195/CA/NCI NIH HHS/United States

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