Superfund Research Program
Title: Super-Enhancer-mediated Control of Liver Fibrosis by BET Bromodomain Proteins
Accession Number: SRP043435
Link to Dataset: https://trace.ncbi.nlm.nih.gov/Traces/sra/?study=SRP043435
Repository: Sequence Read Archive (SRA)
Data Type(s): Nucleotide Sequence
Organism(s): Homo sapiens
Summary: 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. Overall design: 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.
Publication(s) associated with this dataset:- Ding N, Hah N, Yu RT, Sherman MH, Benner CW, Leblanc M, He M, Liddle C, Downes M, Evans RM. 2015. BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A 112(51):15713-15718. doi:10.1073/pnas.1522163112 PMID:26644586 PMCID:PMC4697417
- University of California-San Diego: Toxicogenomic Analysis of Nuclear Xenobiotic Receptors