Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Super-Enhancer-mediated Control of Liver Fibrosis by BET Bromodomain Proteins

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Ruth Yu 

PROVIDER: E-GEOD-58680 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

BRD4 is a novel therapeutic target for liver fibrosis.

Ding Ning N   Hah Nasun N   Yu Ruth T RT   Sherman Mara H MH   Benner Chris C   Leblanc Mathias M   He Mingxiao M   Liddle Christopher C   Downes Michael M   Evans Ronald M RM  

Proceedings of the National Academy of Sciences of the United States of America 20151207 51

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and  ...[more]

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