Project description:Highly accessible genomic super-enhancers often upregulate tumor-promoting genes in cancer, yet the role of genomic variation within them remains unclear. We identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. Our study revealed that a common germline insertion variant within the super-enhancer is associated with better progression-free survival in breast cancer patients and reduced chromatin accessibility at the super-enhancer locus. By deleting the insertion allele in breast cancer cells, we observed increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, delayed cell death, and reduced infiltration of CD80+ pro-inflammatory macrophages—events that promote tumor growth. The absence of the insertion also activated a protumoral transcriptional program through LINC00636 overexpression. Our findings highlight an insertion/deletion variant that fine-tunes the regulatory function of a bifunctional super-enhancer and suggest a protective role for the insertion in breast cancer.
Project description:Highly accessible genomic super-enhancers often upregulate tumor-promoting genes in cancer, yet the role of genomic variation within them remains unclear. We identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. Our study revealed that a common germline insertion variant within the super-enhancer is associated with better progression-free survival in breast cancer patients and reduced chromatin accessibility at the super-enhancer locus. By deleting the insertion allele in breast cancer cells, we observed increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, delayed cell death, and reduced infiltration of CD80+ pro-inflammatory macrophages—events that promote tumor growth. The absence of the insertion also activated a protumoral transcriptional program through LINC00636 overexpression. Our findings highlight an insertion/deletion variant that fine-tunes the regulatory function of a bifunctional super-enhancer and suggest a protective role for the insertion in breast cancer.
Project description:Using GRO-Seq, we find extensive regulation of enhancer RNAs (eRNA) within super-enhancers in response to lipopolysaccharide treatment in macrophages. Both activation and repression of gene expression are associated with super-enhancers and eRNA transcription dynamics. Co-treatment of LPS and the anti-inflammatory drug dexamethasone targeted specific super-enhancers by attenuating their eRNA expression, leading to reduced expression of key inflammatory genes. We propose that super-enhancers function as molecular rheostats integrating the binding profiles of key regulators to produce dynamic profiles of gene expression. Nascent transcriptome (GRO-Seq) analysis over a time course (0, 20, 60, 180 min) of Lipopolisaccharide and Dexamethasone signaling in mouse bone marrow-derived macrophages.
Project description:Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a novel TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
Project description:Although KRAS G12C inhibitors have altered the treatment strategy of patients with KRAS G12C mutant lung cancer, their efficacy is insufficient to eliminate tumors. Here, we identified that inhibition of mutant KRAS promotes escape from macrophage phagocytosis by upregulating the expression of ‘don’t eat me’ signal proteins, including CD47. CD47 was induced by the binding of FOXA1 to the super-enhancer of CD47. The addition of an anti-CD47 antibody restored macrophage phagocytosis and phenotype of macrophages.
Project description:Super enhancer in liver propagates inflammatory signaling by super enhancer-mediatedinducing chemokine expression and is the therapeutic potential of BET inhibition in Alcoholic hepatitis(AH) treatment.
Project description:Super enhancer in liver propagates inflammatory signaling by super enhancer-mediatedinducing chemokine expression and is the therapeutic potential of BET inhibition in Alcoholic hepatitis(AH) treatment.
Project description:Super enhancer in liver propagates inflammatory signaling by super enhancer-mediatedinducing chemokine expression and is the therapeutic potential of BET inhibition in Alcoholic hepatitis(AH) treatment.
Project description:Here, we investigate the role of enhancers in myofibroblasts, a cell type that dominates the pathogenesis and progression of tissue fibrosis. We reveal that bromodomain and extra-terminal family members (BETs), an important group of epigenetic readers, are critical for super-enhancer-mediated pro-fibrotic gene expression in hepatic stellate cells (HSCs, lipid-containing liver-specific pericytes), upon activation during liver fibrogenesis give rise to myofibroblasts2-4. We observe significantly enriched localization of BETs to hundreds of super-enhancers associated with genes involved in multiple pro-fibrotic pathways. This unique loading pattern consequentially serves as a molecular mechanism by which BETs modulate pro-fibrotic gene expression in myofibroblasts. Strikingly, suppression of BET-enhancer interaction using small-molecule inhibitors such as JQ1 dramatically blocks activation of HSCs into myofibroblasts and significantly compromises the proliferation of activated HSCs. Identification of BRD2, BRD3, BRD4, PolII, PolIIs2p and PolIIs5p binding sites in human stellate LX2 cells that were treated with DMSO (0.1%) or JQ1 (500nM) for 16 hrs.
