Project Details
Description
PROJECT SUMMARY / ABSTRACT
Cholestatic fibrogenesis is a pathobiological process of the bile ducts, characterized by biliary strictures,
cholestasis, and progressive peri-portal fibrosis. During biliary fibrosis, diseased cholangiocytes become
highly secretory, releasing a variety of paracrine signaling molecules that subsequently activate hepatic
stellate cells (HSC). Progression toward end stage disease is characterized by an exaggerated fibrogenic
response to chronic injury, culminating in peri-portal deposition of matrix molecules that progresses to
biliary cirrhosis. We have also shown that the cholangiocyte secretome, which mediates the crosstalk,
depends heavily on regulatory mechanisms involving epigenetic enzymes and long non-coding RNAs
(lncRNAs) to modify chromatin. The ensuing histone modifications in cholangiocytes drive transcription of
pathological gene networks that perpetuate fibrosis. The novel direction described here supports the
concept that TGF-β induced lncRNAs in cholangiocytes can serve either as decoy lncRNAs to prevent
engagement of chromatin silencers (e.g., enhancer of zeste homologue 2, EZH2) or as guide lncRNAs to
engage chromatin activators (e.g., lysine acetyl transferase 2A, KAT2A). We have generated the following
novel preliminary data: i) Pathologic TGF-β signaling induces upregulation of 267 lncRNAs in
cholangiocytes, including TILC and TGFB2-AS1; ii) A network of cholangiocyte-derived paracrine
activators of HSCs are regulated by histone modifiers and lncRNAs as demonstrated by chromatin
immunoprecipitation sequencing (ChIP-seq), RNA-sequencing (RNA-seq) and RNA immunoprecipitation
(RIP); iii) Biliary organoids derived from MDR2 knockout (KO) mice demonstrate distinct upregulation of
lncRNAs; and iv) Biliary fibrosis is exacerbated in EZH2 KO mice and blunted in KAT2A KO mice. Based
on this preliminary data, we propose the central hypothesis that dysregulated cholangiocyte lncRNAs
orchestrate the cholangiocyte epigenome to amplify production of a fibrogenic secretome. In Aim I, we will
test the subhypothesis that a decoy lncRNA prevents gene silencing by excluding EZH2 from chromatin.
In Aim II, we will evaluate the subhypothesis that a guide lncRNA recruits KAT2A to chromatin to promote
a fibrogenic secretome. In Aim III, we will investigate the subhypothesis that targeting specific lncRNAs
will prevent fibrogenesis in mouse models and human organoids. In summary, we propose the novel
concept that lncRNA dysregulation influences key epigenetic regulators in cholangiocytes to modify
chromatin and drive transcription of a fibrogenic gene network. Interventions targeting these newly
discovered pathways with RNA therapeutics may have the capability to prevent or reverse specific
molecular events that underlie biliary fibrosis.
Status | Active |
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Effective start/end date | 2/15/19 → 1/31/25 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $321,975.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $351,045.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $357,750.00
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