Project description:To examine the changes in RNA expression profile under AhR antagonist treatment in human hematopoietic stem progenitor cells (HSPCs), CD34+cells were isolated from umbilical cord blood (UCB) unit. CD34+cells were cultured with two different AhR antagonists CH223191 and StemRegenin1 (SR1) ex vivo for 7 days. cultured cells were used to perform RNA sequencing and analyze the changes in RNA expression profile by treatment.
Project description:High-throughput data analysis was performed to identify the differentially expressed circRNAs in K1 control cell and AhR antagonist treated K1 cells. In total, 45 differentially expressed circRNAs were found.
Project description:RNA-seq was done on eight different lymphoblastoid cell lines for vehicle control, 3-MC agonist treatment and GNF-351 antagonist treatment for AHR to look at AHR regulated genes with different genetic backgrounds. We identified 69 genes that were highly differentially expressed after 3-MC or GNF-351 antagonist treatment with variation in the degree fo differential expression between the eight cell lines.
Project description:Indole-3-pyruvate (I3P), an endogenous metabolite derived from tryptophan by gut microbiota and IL4I1 enzyme in humans can potentially activate the transcriptional activity of the Aryl Hydrocarbon receptor. Here we test this by stimulating AHR proficient U-87MG cells with I3P alone or in combination with the AHR antagonist SR1.
Project description:SJL pregnant mice were infected with Zika virus and treated with nanoliposomes loaded with AHR antagonist CH223191 or control nanoliposomes. RNA-Seq analysis was performed in CNS samples from the pups.
Project description:BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset.
Project description:The goal of the study was to identify genes that are directly or indirectly coregulated by the AhR pathway in primary human AML cells. Patient AML cells were treated for 16 hours with the two indirubin derivatives 6-bromoindirubin-3'oxime (BIO), 1-Methyl-6-bromoindirubin-3'oxime (MeBIO), the AHR-antagonist SR1 (StemReginin1), combinations of BIO+SR1 and MeBIO+SR1 or DMSO alone at indicated concentrations prior to RNA extraction for sequencing. RNA-Seq performed on 5 primary AML samples fresh (t0) and after exposure to AhR-agonists (2), -antagonist (1), and DMSO Contributor: Leucegene Project, IRIC