Transcriptional microarray analysis was conducted on gastrocnemius muscle of control and PGC-1(i)skm-/- mice one week after the last tamoxifen administration using the Affymetrix Mouse Gene 1.0 ST.
The transcriptional coregulator PGC-1β controls mitochondrial function and anti-oxidant defence in skeletal muscles.
Specimen part
View SamplesWe compared the transcriptional profile of mammary tumors spontaneously developed in PyMT transgenic mice either bearing or not additional copies of the endogeneous SIRT6 gene.
SIRT6 Suppresses Cancer Stem-like Capacity in Tumors with PI3K Activation Independently of Its Deacetylase Activity.
Sex, Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Medial HOXA genes demarcate haematopoietic stem cell fate during human development.
Specimen part
View SamplesThe derivation of functional, transplantable HSCs from an pluripotent stem cells in vitro holds great promise for clinical therapies, but is unachieved. In order to achieve full functionality of HSCs, it is vital to determine the extent to which PSCs can currently be differentiated to the HSC program in vitro and identify the remaining dysregulated genetic pathways.
Medial HOXA genes demarcate haematopoietic stem cell fate during human development.
Specimen part
View SamplesRA signalling regulated endothelial to hematopoietic transition and HSC generation. Overall design: EB- or FL-derived HSPC were profiled before (d0) or after (d6) 6 days of treatment with 0.2uM AM580 on OP9, and after 6 additional days of expandion of OP9 (d12) without treatment.
Medial HOXA genes demarcate haematopoietic stem cell fate during human development.
No sample metadata fields
View SamplesHOXA7 regulates FL-HSPC self-renewal in vitro and in vivo. We profiled EB-HSPCs after HOXA7 overexpression (EB-HOXA7), or with a control vector (EB-CTR), to assess the gene expression programs regulated by HOXA7. Overall design: CD34+CD38-CD43+CD90+ HSPCs were infected with lentiviral FUGW vector either empty (FUGW-GFP) or encoding HOXA7(FUGW-GFP-HOXA7) protein. Cells were expanded on op9 for 15 days and than sorted for GFP HSPC immunophenotype.
Medial HOXA genes demarcate haematopoietic stem cell fate during human development.
No sample metadata fields
View SamplesRole of CTCF in activated B cells. Overall design: Transcriptome profiling of CTCF deficient and proficient activated in vitro B cells.
CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation.
Specimen part, Subject
View SamplesTo identify novel LXR target genes, we conducted transcriptional profiling studies using RAW264.7 cells ectopically expressing
Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.
Cell line
View SamplesBRAF 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. Overall design: Total RNA isolated from 12 human melanoma cell lines (501Mel) after different treatments was subjected to multiplexed RNA-sequencing using Illumina NextSeq500 sequencing tehnology.
Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma.
Specimen part, Cell line, Subject
View SamplesCastrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance in early prostate cancer, other factors such as c-Myc and the E2F family also play a role in later stage disease. Hes6 is a transcription co-factor that has been associated with neurogenesis during gastrulation, a neuroendocrine phenotype in the prostate and metastasis in breast cancer but its role in prostate cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and AR and drives castration resistance in prostate cancer. Hes6 activates a cell-cycle enhancing transcriptional network that maintains tumour growth and nuclear AR localization in castrate conditions. We show aphysical interaction between E2F1 and both Hes6 and AR, and suggest a co-dependency of these transcription factors in castration-resistance. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted. We have therefore shown for the first time the critical role of Hes6 in the development of CRPC and identified its potential in patient specific therapeutic strategies.
HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network.
Specimen part, Disease, Cell line
View Samples