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1.
bioRxiv ; 2023 Jul 07.
Article in English | MEDLINE | ID: mdl-37461589

ABSTRACT

The intracellular Gram-negative bacterium Coxiella burnetii replicates within macrophages and causes a zoonotic disease known as Q fever. In murine macrophages, the cytokine tumor necrosis factor (TNF) is critical for restriction of intracellular C. burnetii replication. Here, we show that TNF collaborates with type I interferon (IFN) signaling for maximal control of C. burnetii. We found that TNF and type I IFN upregulate the expression of the metabolic enzyme immune responsive gene 1 (IRG1), also known as cis-aconitate decarboxylase 1 (ACOD1), and that IRG1 is required to restrict C. burnetii T4SS translocation and replication within macrophages. Further, we show that itaconic acid, the metabolic product of IRG1, restricts C. burnetii replication both intracellularly and in axenic culture. These data reveal that TNF and type I IFN upregulate the IRG1-itaconate pathway to restrict intracellular C. burnetii replication within murine macrophages.

2.
Cell Rep ; 34(10): 108855, 2021 03 09.
Article in English | MEDLINE | ID: mdl-33691120

ABSTRACT

Immune responses must be tightly regulated in order to avoid excessive inflammation. In this issue of Cell Reports, Bambouskova et al. (2021) demonstrate that itaconate and iNOS collaborate to tolerize the NLRP3 inflammasome, thereby limiting cytokine secretion and cell death.


Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Humans , Inflammation , Succinates
3.
Nat Microbiol ; 5(3): 528, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32042131

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
J Mol Biol ; 431(1): 111-121, 2019 01 04.
Article in English | MEDLINE | ID: mdl-30098338

ABSTRACT

Cell-type specific gene expression programs are tightly linked to epigenetic modifications on DNA and histone proteins. Here, we used a novel CRISPR-based epigenome editing approach to control gene expression spatially and temporally. We show that targeting dCas9-p300 complex to distal non-regulatory genomic regions reprograms the chromatin state of these regions into enhancer-like elements. Notably, through controlling the spatial distance of these induced enhancers (i-Enhancer) to the promoter, the gene expression amplitude can be tightly regulated. To better control the temporal persistence of induced gene expression, we integrated the auxin-inducible degron technology with CRISPR tools. This approach allows rapid depletion of the dCas9-fused epigenome modifier complex from the target site and enables temporal control over gene expression regulation. Using this tool, we investigated the temporal persistence of a locally edited epigenetic mark and its functional consequences. The tools and approaches presented here will allow novel insights into the mechanism of epigenetic memory and gene regulation from distal regulatory sites.


Subject(s)
CRISPR-Associated Proteins/genetics , CRISPR-Cas Systems/genetics , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , E1A-Associated p300 Protein/genetics , Gene Editing/methods , Cell Line , Gene Expression Regulation , HEK293 Cells , Humans , Promoter Regions, Genetic/genetics , RNA, Guide, Kinetoplastida/genetics
5.
Nat Commun ; 9(1): 4275, 2018 10 15.
Article in English | MEDLINE | ID: mdl-30323222

ABSTRACT

Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.


Subject(s)
Antineoplastic Agents/pharmacology , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Combinatorial Chemistry Techniques , Drug Delivery Systems , Gene Knockout Techniques , Genetic Testing , Models, Biological , Pancreatic Neoplasms/genetics , Animals , Cell Cycle Checkpoints , Cell Death , Cell Line, Tumor , Drug Synergism , Humans , Mice, Nude , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Reproducibility of Results
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