IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48647-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)
    National University of Singapore
    National University of Singapore)

  • Euodia Lim

    (Agency for Science, Technology and Research (A*STAR)
    National University of Singapore)

  • María Clara Miserendino

    (Universidad Nacional de Córdoba
    A*STAR)

  • Yaw Sing Tan

    (A*STAR)

  • Shawn Hoon

    (A*STAR)

  • Adrian Kee Keong Teo

    (Agency for Science, Technology and Research (A*STAR)
    National University of Singapore
    National University of Singapore
    National University of Singapore)

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.

Suggested Citation

  • 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 & Adrian Kee Keong Teo, 2024. "HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48647-w
    DOI: 10.1038/s41467-024-48647-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48647-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-48647-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Isidoro Cobo & Paola Martinelli & Marta Flández & Latifa Bakiri & Mingfeng Zhang & Enrique Carrillo-de-Santa-Pau & Jinping Jia & Víctor J. Sánchez-Arévalo Lobo & Diego Megías & Irene Felipe & Natalia , 2018. "Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas," Nature, Nature, vol. 554(7693), pages 533-537, February.
    2. Hwee Hui Lau & Nicole A. J. Krentz & Fernando Abaitua & Marta Perez-Alcantara & Jun-Wei Chan & Jila Ajeian & Soumita Ghosh & Yunkyeong Lee & Jing Yang & Swaraj Thaman & Benoite Champon & Han Sun & Alo, 2023. "PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Jing Zhang & Donghoon Lee & Vineet Dhiman & Peng Jiang & Jie Xu & Patrick McGillivray & Hongbo Yang & Jason Liu & William Meyerson & Declan Clarke & Mengting Gu & Shantao Li & Shaoke Lou & Jinrui Xu &, 2020. "An integrative ENCODE resource for cancer genomics," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. Vikas Chandra & Pengxiang Huang & Nalini Potluri & Dalei Wu & Youngchang Kim & Fraydoon Rastinejad, 2013. "Multidomain integration in the structure of the HNF-4α nuclear receptor complex," Nature, Nature, vol. 495(7441), pages 394-398, March.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Michelle Dietzen & Haoran Zhai & Olivia Lucas & Oriol Pich & Christopher Barrington & Wei-Ting Lu & Sophia Ward & Yanping Guo & Robert E. Hynds & Simone Zaccaria & Charles Swanton & Nicholas McGranaha, 2024. "Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Buki Kwon & Mervin M. Fansler & Neil D. Patel & Jihye Lee & Weirui Ma & Christine Mayr, 2022. "Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Lianjun Zhang & Le Xuan Truong Nguyen & Ying-Chieh Chen & Dijiong Wu & Guerry J. Cook & Dinh Hoa Hoang & Casey J. Brewer & Xin He & Haojie Dong & Shu Li & Man Li & Dandan Zhao & Jing Qi & Wei-Kai Hua , 2021. "Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Guang Shi & D. Thirumalai, 2023. "A maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Jason P. Wray & Elitza M. Deltcheva & Charlotta Boiers & Simon Е Richardson & Jyoti Bikram Chhetri & John Brown & Sladjana Gagrica & Yanping Guo & Anuradha Illendula & Joost H. A. Martens & Hendrik G., 2022. "Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Hannah L. Harris & Huiya Gu & Moshe Olshansky & Ailun Wang & Irene Farabella & Yossi Eliaz & Achyuth Kalluchi & Akshay Krishna & Mozes Jacobs & Gesine Cauer & Melanie Pham & Suhas S. P. Rao & Olga Dud, 2023. "Chromatin alternates between A and B compartments at kilobase scale for subgenic organization," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Jiapei Yuan & Yang Tong & Le Wang & Xiaoxiao Yang & Xiaochuan Liu & Meng Shu & Zekun Li & Wen Jin & Chenchen Guan & Yuting Wang & Qiang Zhang & Yang Yang, 2024. "A compendium of genetic variations associated with promoter usage across 49 human tissues," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Isidoro Cobo & Sumit Paliwal & Cristina Bodas & Irene Felipe & Júlia Melià-Alomà & Ariadna Torres & Jaime Martínez-Villarreal & Marina Malumbres & Fernando García & Irene Millán & Natalia Pozo & Joo-C, 2023. "NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Zoe Veneti & Virginia Fasoulaki & Nikolaos Kalavros & Ioannis S. Vlachos & Christos Delidakis & Aristides G. Eliopoulos, 2024. "Polycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Dasol Han & Guojing Liu & Yujeong Oh & Seyoun Oh & Seungbok Yang & Lori Mandjikian & Neha Rani & Maria C. Almeida & Kenneth S. Kosik & Jiwon Jang, 2023. "ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48647-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.