Project description:Long non-coding RNAs have been implicated in many of the hallmarks of cancer. We previously annotated lncRNA152 (lnc152; a.k.a. DRAIC) and demonstrated its roles in proliferation, cell cycle progression, and regulation of the estrogen signaling pathway in breast cancer cells. Herein, we found that lnc152 is highly upregulated in luminal breast cancers, but is downregulated in triple-negative breast cancers (TNBC). Using a set of complementary experimental approaches, we found that knockdown of lnc152 promotes cell migration and invasion in luminal breast cancer cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In xenograft studies in mice, lnc152 inhibited the growth and metastasis of TNBC cells. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes regulating cancer-related phenotypes, including angiogenesis. Using RNA-pull down assays coupled with LC-MS/MS analysis, we identified RBM47, a known tumor suppressor protein in breast cancer, as a lnc152-interacting protein. We found that lnc152 suppresses the aggressive phenotypes of TNBC cells by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC.
Project description:Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFN) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.
Project description:Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFN) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.
Project description:Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFN) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.
Project description:Unveiling the regulatory pathways maintaining hepatic stellate cells (HSC) in a quiescent (q) phenotype is essential to develop new therapeutic strategies to treat fibrogenic diseases. To uncover the miRNA-mRNAs regulatory interactions in qHSCs, HSCs were FACS-sorted from healthy livers and activated HSCs were generated in vitro. MiRNA Taqman array analysis showed HSCs expressed a low number of miRNA, from which 46 were down-regulated and 212 up-regulated upon activation. Computational integration of miRNA and gene expression profiles revealed that 66% of qHSCs miRNAs correlated with more than 6 altered targeted mRNAs (17,28±10,7 targets/miRNA), whereas aHSC-associated miRNAs had an average of 1,49 targeted genes. Interestingly, interaction networks generated by miRNA-targeted genes in qHSCs were associated with key HSCs activation processes. Next, selected miRNAs were validated in healthy and cirrhotic human livers and miR-192 was chosen for functional analysis. Down-regulation of miR-192 in HSC was found to be an early event during fibrosis progression in mouse models of liver injury. Moreover, mimic assays for miR-192 in HSCs revealed its role in HSC activation, proliferation and migration. Together, these results uncover the importance of miRNAs in the maintenance of qHSC phenotype and form the basis for understanding the regulatory networks in HSCs. Transcriptomic profile derived from four quiescent hepatic stellate (QHSC), four activated hepatic stellate (AHSC), three liver sinusoidal endothelial (LSEC) and two hepatocytes cells (HEP).
Project description:Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities, and also via their ability to recruit and activate other cell types. Here, we report the results of a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, which identified CLEC16A, a gene linked to MS susceptibility, as a suppressor of NF-B signaling. Gene and small molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multi-omic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocytespecific Clec16a inactivation increased NF-κB, NLRP3 and gasdermin D activation in vivo, worsening experimental autoimmune encephalomyelitis, a mouse model of MS. Moreover, we detected disrupted mitophagic capacity and gasdermin D activation in astrocytes in samples from individuals with MS. These findings identify CLEC16A as a suppressor of astrocyte pathologic responses and a candidate therapeutic target in MS.