Project description:Transcriptome analysis of: 1- WM1716 melanoma cell line transfected with scrambled control or with miR-211. 2- WM3682 cell line mono-cultured or co-cultured with adipocytes.
Project description:We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Synthesis and biological characterization show that these are PPARα/γ dual agonists. Herein we report the gene expression data from human SGBS pre-adipocytes, stimulated to differentiate with 1, 2 or the classical PPARγ agonist rosiglitazone. The transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines.
Project description:Biased signaling and ligand bias, often referred to as functional selectivity or selective nuclear receptor modulation, have been reported for many nuclear receptor partial agonists over the past 20 years. However, whether differences in nuclear receptor signaling produced by partial and full agonists results from less intense partial agonist modulation, off-target effects, or biased signaling remains unclear. To determine whether biased signaling can occur through nuclear receptors we compare the transcriptional effects of two full agonists (which also favor different coactivator peptides) in human adipocytes. We also test the signaling effects of a partial agonist relative to full agonists. Furthermore, whether biased coactivator peptide recruitment translates to biased signaling in cells has not been determined. In a step towards this goal, we show that these same full agonists induce biased recruitment of 100-300 residue regions of coactivators containing all their nuclear receptor binding motifs. Together these data support the idea that nuclear receptor agonists can induce biased signaling through differences in coactivator recruitment.
Project description:Duchenne Muscular Dystrophy (DMD) is a severe X-linked muscle-wasting disorder characterized by chronic inflammation, progressive fibrosis, and impaired muscle regeneration. The TGFb pathway is overactivated in DMD and it sustains the accumulation of extracellular matrix (ECM), contributing to fibrosis. Our previous results showed that SETDB1 regulates the expression of TGFb-dependent secreted factors impacting fibrosis and myogenic differentiation. In particular, the conditioned medium (CM) of TGFb-treated myotubes impairs myoblasts differentiation and increase fibrosis. In this study, we performed a thorough proteomic analysis of the secretome from DMD myotubes under TGFb stimulation, with or without SETDB1 LOF, to identify secreted factors involved in the dysregulated regenerative environment of DMD. We found that SETDB1 modulates the TGFb-induced secretome, particularly by regulating ECM-related proteins. Among these, we identified EMILIN1, an ECM glycoprotein not previously studied in skeletal muscle. EMILIN1 is upregulated by TGFb reduced upon SETDB1 depletion and more abundant in DMD myotubes. Functional analyses revealed that EMILIN1 LOF impairs late myogenic differentiation and reduces the expression of the fibrotic marker SERPINE1. These findings highlight EMILIN1 as a secreted regulator of myogenesis and fibrosis, and support the role of SETDB1 in regulating the TGFb-dependent secretome in DMD. This study provides new insights into the molecular players contributing to the fibrotic and regenerative defects in DMD, offering potential therapeutic targets for disease intervention.