Ng, N. H. J., Ghosh, S., Bok, C. M., Ching, C., Low, B. S. J., Chen, J. T., Lim, E., Miserendino, M. C., Tan, Y. S., Hoon, S., Teo, A. K. K. (2024). HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-48647-w
Abstract:
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.
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Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research/project is supported by National Medical Research Council through the Open Fund Young Individual Research Grant
This research/project is supported by A*STAR Career Development Fund
This research / project is supported by the A*STAR Singapore Pre-Graduate Award (SIPGA) - NA
Grant Reference no. : NA
This research/project is supported by IMCB, A*STAR, FY2019 SingHealth Duke-NUS Surgery Academic Clinical Programme Research Support Programme Grant, Precision Medicine and Personalised Therapeutics Joint Research Grant 2019, the 2nd A*STAR-AMED Joint Grant Call 192B9002, National Medical Research Council's Open Fund - Individual Research Grant, A*STAR's Manufacturing, Trade, and ConnectivityIndividual Research Grant,
This research/project is supported by FY 2022 Interstellar Initiative Beyond grant