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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Global transcriptional profiles of WT and HOIL-1L-/- BMDMs in response to LPS and TNFa

ABSTRACT: HOIL-1L is an essential member of the linear ubiquitin assembly complex (LUBAC), which targets Nemo for linear ubiquitination during NF-kB activation in response to a variety of simuli, including LPS and TNFa treatment. HOIL-1L has also been suggested to function as a transcription factor. Here we analyzed changes in the global transcriptional profiles of primary bone marrow derived macrophage (BMDMs) from WT and HOIL-1L-/- mice upon treatment with NF-kB activating simuli. BMDMs were differentiated for 1 week and then treated with mock (untreated), 10ng/ml LPS, or 1ng/ml TNFa for 4 hours. RNA was immediately collected and analyzed in biological duplicates by the Agilent 8x60 mouse array.

ORGANISM(S): Mus musculus

SUBMITTER: Mary Rodgers

PROVIDER: E-GEOD-57180 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Global transcriptional profiles of WT and HOIL-1L-/- BMDMs in response to LPS and TNFa

Project description:HOIL-1L is an essential member of the linear ubiquitin assembly complex (LUBAC), which targets Nemo for linear ubiquitination during NF-kB activation in response to a variety of simuli, including LPS and TNFa treatment. HOIL-1L has also been suggested to function as a transcription factor. Here we analyzed changes in the global transcriptional profiles of primary bone marrow derived macrophage (BMDMs) from WT and HOIL-1L-/- mice upon treatment with NF-kB activating simuli.

2014-05-15 | GSE57180 | GEO

The linear ubiquitin chain assembly complex LUBAC generates heterotypic ubiquitin chains

Project description:The linear ubiquitin chain assembly complex (LUBAC) is the only known ubiquitin ligase that generates linear/Met1-linked ubiquitin chains. One of the LUBAC components, HOIL-1L, was recently shown to catalyse oxyester bond formation between the C-terminus of ubiquitin and some substrates. However, oxyester bond formation in the context of LUBAC has not been directly observed. We present the first 3D reconstruction of LUBAC obtained by electron microscopy and report its generation of heterotypic ubiquitin chains containing linear linkages with oxyester-linked branches. We found that addition of the oxyester-bound branches depends on HOIL-1L catalytic activity. We suggest a coordinated ubiquitin relay mechanism between the HOIP and HOIL-1L ligases supported by cross-linking mass spectrometry data, which show proximity between the catalytic RBR domains. Mutations in the linear ubiquitin chain-binding NZF domain of HOIL-1L reduces chain branching confirming its role in the process. In cells, these heterotypic chains were induced by TNF. In conclusion, we demonstrate that LUBAC assembles heterotypic ubiquitin chains with linear and oxyester-linked branches by the concerted action of HOIP and HOIL-1L.

2021-06-28 | PXD019771 | Pride

Transcription of Tnfaip3 is regulated by NF-kB and p38 via C/EBPβ in activated macrophages

Project description:Macrophages play a pivotal role in the immune system through recognition and elimination of microbial pathogens. Toll-like receptors (TLRs) on macrophages interact with microbial substances and initiate signal transduction through intracellular adapters. TLR4, which is important for the response to lipopolysaccharide (LPS), triggers downstream signaling mediators and eventually activates IkB kinase (IKK) complex and mitogen-activated protein kinases (MAPKs) such as p38. Previous reports revealed that, in addition to NF-kB, the induction of some LPS-inducible genes in macrophages required another transcription factor whose activity depends on p38. However, these transcription factors remained to be identified. Among these genes, NF-kB and C/EBPβ, a p38 downstream transcription factor, were predicted to co-regulate genes in LPS-stimulated BMDMs. Based on the subsequent results of a chromatin immunoprecipitation assay, we demonstrated that Tnfaip3 is regulated by both NF-kB and p38-dependent C/EBPβ. These results elucidate our understanding of the tight regulation of innate immunity. In order to identify p38-activated transcription factors that cooperate with NF-kB in response to LPS stimulation, microarrays were used to identify genes regulated by both NF-kB and p38 using wild-type, IKK-depleted, and p38 inhibitor-treated mouse bone marrow-derived macrophages (BMDMs). In silico analysis of transcription factor binding sites was used to predict the potential synergistic transcription factors from the co-expressed genes.

2015-04-28 | E-GEOD-46361 | biostudies-arrayexpress

Mus musculus

Project description:Global transcriptional profiles of WT and HOIL-1L-/- BMDMs in response to LPS and TNFa

| PRJNA245855 | ENA

The specifcity of innate immune response is enforced by repression of interferon-response elements by NFkB p50

Project description:The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. The transcription factors nuclear factor kB (NF-kB) and the interferon (IFN) regulatory factors (IRFs) bind to the kB site and the interferon response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-kB p50 homodimer (p50:p50) as a regulator of IRF responses. First, unbiased genome-wide expression analysis revealed that p50 repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences, which was substantiated by biochemical and structural analyses. Second, mathematical modeling predicted that p50:p50 might enforce the stimulus-specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-b was rendered stimulus-specific by the binding of p50:p50 to the G-IRE–containing IFNb enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-b in response to bacterial DNA sensed by Toll-like receptor 9. This role for NF-kB p50 in enforcing the specificity of the cellular response to pathogens by binding to a previously uncharacterized subset of IRE sequences alters our understanding of how the NF-kB and IRF signaling systems cooperate to regulate antimicrobial immunity. [BMDM]: Total RNA extracted from wt, p50-/- or ifnar-/- bone marrow derived macrophages (BMDMs) were subjected to stimulation with LPS, CpG or IFNb [MEF]: Total RNA extracted from wt or p50KO primary mouse embryonic fibroblasts were subjected to stimulation with LPS or IFNb

2011-03-01 | E-GEOD-27112 | biostudies-arrayexpress

Bone Marrow Derived Macrophages(BMDMs) transcriptome analysis of control, LPS and LPS plus BHB group

Project description:Purpose: The purpose of this study was to compare the BMDMs transcriptome in the control LPS and LPS plus BHB group in order to identify the critical pathway that contributed to the inhibiton of BHB on M1 polarization. Methods: 1× 106 BMDMs were pre-treated with PBS or BHB for 1 hours before LPS administration. Four hours later, BMDMs were harvested for RNA preparation. Results: Among 16650 mapped genes, 7325 differentially expressed genes were identified, including 244 LPS inducible BHB down regulated named class A and 537 LPS repressed BHB up regulated genes named class B. The genes in class A were mainly TLR4 and TNF signaling pathway, while genes in class B were associated with negative regulation of transcription and NF-KB signaling. The GSEA showed that BHB have the similar profiles chnage on BMDMs with TSA. Conclusions: Our study revealed that BHB down regulated TLR4 and NF-KB pathway related genes to inhibited M1 polarization, and BHB have a similar effect on BMDMs with TSA through comparing the genetic changes of two substance caused in cells.

2022-04-06 | GSE152241 | GEO

Genome wide Affymetric Microarray analysis for RIPK1 dependent inflammatory changes in Bone Marrow Derived Macrophages (BMDMs)

Project description:Gene level expression estimate using the Whole Transcript (WT) Assay approach of the Gene 1.0 ST Array System for Mouse. This assay was done to identify the RIPK1-dependent gene expression changes in mouse BMDMs. Cost-effective gene-level analysis based on whole-transcript coverage. We analyzed Bone Marrow Derived Macrophages (BMDMs) under 4 different conditions (Control, LPS, LPS/zVAD, LPS/zVAD/Nec-1) to assess inflammatory changes in RIPK1 kinase dependent manner compared to LPS, LPS/zVAD plus RIPK1 inhibitor Nec-1 and control.

2016-09-07 | E-GEOD-72797 | biostudies-arrayexpress

In vitro response of fibroblasts isolated from patients with RBCK1 deficiency

Project description:Loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1) results in disruption of the linear ubiquitination assembly complex (LUBAC). Impairment of LUBAC results in impaired NF-kB activation in response to TNF and IL-1b in fibroblastic cells, but also display enhanced pro-inflammatory responses to TNF and IL-1b in leukocytes. Autosomal recessive complete human HOIL-1/RBCK1 deficiency is a new disorder with unbalanced cellular responses to pro-inflammatory cytokines, resulting in the paradoxical association of auto-inflammation and pyogenic bacterial disease, as well as the surprising development of muscular amylopectinosis. The genome-wide gene expression analysis showed that human HOIL-1 deficiency results in impaired NF-B activation in response to TNF- and IL-1 in fibroblastic cells.

2014-10-01 | GSE31064 | GEO

ChIPseq to profile CDK9 and Hes1 occupancy in bone marrow-derived macrophages from C57BL/6 mice

Project description:We characterized the CDK9 and Hes1 occupancy on gene loci in conditions of unstimuated and LPS stimualtion in BMDMs BMDMs were left untreated or stimulated with LPS for 1 hour. CDK9 or Hes1 ChIP was performed and the DNA products were subject to ChIPseq

2016-06-13 | E-GEOD-77334 | biostudies-arrayexpress

HIF and HOIL-1L-mediated PKCζ degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury

Project description:Exposure to hypoxia requires adaptive mechanisms for survival. During acute hypoxia, Na,K-ATPase endocytosis in alveolar epithelial cells (AEC) occurs via protein kinase C zeta (PKCζ) phosphorylation of α1- Na,K-ATPase independently of the hypoxia inducible factor (HIF). However, exaggerated Na,K-ATPase down-regulation leads to cell death. Here we report that during prolonged hypoxia plasma membrane Na,K-ATPase levels were maintained at ~50% of normoxic values due to HIF mediated regulation of HOIL-1L which targets PKCζ for degradation. Silencing HOIL-1L in the lung epithelium prevented PKCζ degradation causing Na,K-ATPase downregulation. Accordingly, HIF regulation of HOIL-1L targets the phosphorylated PKCζ for degradation and serves as an hypoxia-adaptive mechanism to stabilize the Na,K-ATPase avoiding significant lung injury.

2018-02-14 | GSE102107 | GEO

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