Gut Microbiota Modulation of Regulatory DNA Elements revealed by Massively Parallel Functional Characterization

In liver hepatocytes, CREs enable adaptation to environmental changes by modifying transcriptomes, particularly in response to gut microbiome signals, which are linked to liver diseases. However, our understanding of the functionality of CREs and their responses to gut microbiota signals in vivo remains limited.

To address this, we conducted a genome-wide multiplexed reporter assay (MPRA) to map functional CREs in the liver. Using this functional catalog, we discovered a rare functional variant associated with hepatocellular carcinoma in the Asian population that disrupts CRE activity. Additionally, we identify functional CREs regulated by gut microbiota.