AH. Dr. Cao's lab has developed the most up-to-date technology, CRISPR-dCas9, which uses genomic DNA site-specific gene editing techniques, to regulate specific gene expression under enhancers and superenhancers. The use of these techniques can significantly advance research and clinical practice, particularly in the field of AH. Dr. Cao and his colleagues are currently studying the cause of gradual liver destruction in liver diseases, in particular AH, a highly morbid condition characterized by acute liver injury in the setting of excess alcohol ingestion. Severe AH can lead to acute liver failure and is associated with a 30-day mortality of greater than 30%.
Many cytokines and chemokines are known to be highly upregulated in AH, of which tumor necrosis factor-alpha (TNF-alpha) is a prototypical example. TNF-alpha is highly induced in AH and released by inflammatory cells, possibly Kupffer cells in the liver. TNF-alpha is a trigger for other chemokines in propagating the inflammatory cascade. However, the downstream signaling pathways and regulatory mechanisms related to TNF-alpha signaling remain incompletely understood despite decades of research. Dr. Cao's work has suggested that TNF-alpha may regulate expression of target inflammatory genes via activation of superenhancers. He found a superenhancer that modulates the expression of CXCL chemokines in AH under TNF-alpha stimulation in hepatic sinusoidal endothelial cells, and both the superenhancer and its target genes are under control of histone modifications. This work highlighted the important roles of distal cis-regulatory elements and epigenetic regulation, or lack thereof, in the pathogenesis of AH.