Dissecting and targeting functional epigenetics in liver metabolic disorders

Over-nutrition and inflammation induce transcriptional alterations linked with non-alcoholic fatty liver diseases (NAFLD).

Such pathological changes are tightly controlled by chromatin remodeling events, particularly at non-coding genomic regions in the liver cells. Those tissue-specific regions are enriched with SNPs but their function and regulation remain largely unknown.

The widely used strategies to map active chromatin landscape with epigenetic markers, which have not even been widely applied to human cohorts, are questioned most recently.

Studies by us and others have shown that genomic regions featured with active epigenetic markers, and previously clustered as ‘super enhancers’, are not always functionally identical. Many of them are either inactive or repressive (silencers).

The molecular traits to differentiate the ‘true’ functional enhancers and silencers are unknown, which halts the efforts for deciphering the true roles of genetic risk factors in NAFLD.The OBJECTIVE of my proposal is to characterize NAFLD/NASH-relevant functional epigenetics and to test proof-of-concept enhancer targeting treatment strategies.

We plan to combine molecular techniques and human cohorts to achieve three major AIMs: To identify monocyte and liver epigenetic signatures in NAFLD/NASH cohort.To investigate the functionality of the epigenetic regions in human liver cells.To therapeutically target liver enhancers using tissue-specific oligonucleotides.