Epistasis of transcriptomes reveals synergism between transcriptional activators Hnf1α and Hnf4α

Abstract

The transcription of individual genes is determined by combinatorial interactions between DNA-binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1α and Hnf4α control pancreatic islet b-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1a and Hnf4a functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1α+/- or pancreas-specific Hnf4α mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1a on Hnf4α gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1a and Hnf4α regulate common targets synergistically. Hnf1a binding in Hnf4α-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1α and Hnf4α control a common islet-cell regulatory program that is defective in human monogenic diabetes. © 2010 Boj et al.