Hnf4a mediates microbial control of intestinal gene expression and inflammation

Abstract

Microbiota influence diverse aspects of intestinal epithelial physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of host gene expression are poorly understood. Using an unbiased screening strategy, we found that the zebrafish Hepatic nuclear factor 4 alpha (Hnf4a) transcription factor specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis disclosed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells revealed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of Hnf4a and Hnf4g occupancy. Interspecies meta-analysis suggests Hnf4a may mediate microbial contributions to inflammatory bowel disease pathogenesis. These results indicate Hnf4a plays a critical conserved role in maintaining intestinal homeostasis in response to microbiota and inflammation.