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

Natasha Hui Jin Ng, Soumita Ghosh, Chek Mei Bok, Carmen Ching, Blaise Su Jun Low, Juin Ting Chen, Euodia Lim, María Clara Miserendino, Yaw Sing Tan, Shawn Hoon and Adrian Kee Keong Teo ()
Additional contact information
Natasha Hui Jin Ng: Agency for Science, Technology and Research (A*STAR)
Soumita Ghosh: National University of Singapore
Chek Mei Bok: Agency for Science, Technology and Research (A*STAR)
Carmen Ching: Agency for Science, Technology and Research (A*STAR)
Blaise Su Jun Low: Agency for Science, Technology and Research (A*STAR)
Juin Ting Chen: Agency for Science, Technology and Research (A*STAR)
Euodia Lim: Agency for Science, Technology and Research (A*STAR)
María Clara Miserendino: Universidad Nacional de Córdoba
Yaw Sing Tan: A*STAR
Shawn Hoon: A*STAR
Adrian Kee Keong Teo: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-48647-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48647-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-48647-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().