HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes

• Published in: Nature communications Vol. 15; no. 1; pp. 4288 - 21
• Main Authors: Ng, Natasha Hui Jin, Ghosh, Soumita, Bok, Chek Mei, Ching, Carmen, Low, Blaise Su Jun, Chen, Juin Ting, Lim, Euodia, Miserendino, María Clara, Tan, Yaw Sing, Hoon, Shawn, Teo, Adrian Kee Keong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 38/89; 49/15; 631/136/142; 631/532/1360; A Kinase Anchor Proteins - genetics; A Kinase Anchor Proteins - metabolism; Animals; Beta cells; Binding; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genomes; Health risks; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Insulin-Secreting Cells - metabolism; Liver; Mice; multidisciplinary; Organ Specificity - genetics; Pancreas; Pleiotropy; Science; Science (multidisciplinary); Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48647-w

HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known ( ACY3 , HAAO, HNF1A , MAP3K11 ) and previously unidentified ( ABCD3 , CDKN2AIP , USH1C , VIL1 ) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1 , GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation. Here, the authors generated a genome-wide map of the global targets bound by HNF4A and HNF1A in beta cells and hepatic cells, and highlighted notable downstream pathways and target genes that may influence beta cell function. This approach also shed light on a potentially activating effect of a HNF4A type 2 diabetes risk variant.