IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58714-5.html
   My bibliography  Save this article

The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis

Author

Listed:
  • Iriscilla Ayala

    (University of Texas Health San Antonio)

  • Skanda K. Hebbale

    (University of Texas Health San Antonio)

  • Juho Mononen

    (University of Eastern Finland)

  • Madelaine C. Brearley-Sholto

    (University of California Los Angeles)

  • Christopher E. Shannon

    (University of Texas Health San Antonio
    University College Dublin)

  • Ivan Valdez

    (University of Texas Southwestern Medical Center)

  • Marcel Fourcaudot

    (University of Texas Health San Antonio)

  • Terry M. Bakewell

    (University of Texas Health San Antonio)

  • Anna Zagorska

    (Gilead Sciences)

  • Giovanna Romero

    (University of Texas Health San Antonio)

  • Mara Asmis

    (University of Texas Health San Antonio)

  • Fatima A. Musa

    (University of Texas Health San Antonio)

  • Jonah T. Sily

    (University of Texas Health San Antonio)

  • Annie A. Smelter

    (University of Texas Health San Antonio)

  • Edgar A. Hinostroza

    (University of Texas Health San Antonio)

  • Leandro C. Freitas Lima

    (University of Texas Health San Antonio)

  • Thomas Q. Aguiar Vallim

    (University of California Los Angeles)

  • Sami Heikkinen

    (University of Eastern Finland)

  • Luke Norton

    (University of Texas Health San Antonio
    University of Texas Health San Antonio)

Abstract

The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease.

Suggested Citation

  • Iriscilla Ayala & Skanda K. Hebbale & Juho Mononen & Madelaine C. Brearley-Sholto & Christopher E. Shannon & Ivan Valdez & Marcel Fourcaudot & Terry M. Bakewell & Anna Zagorska & Giovanna Romero & Mar, 2025. "The Spatial Transcriptional Activity of Hepatic TCF7L2 Regulates Zonated Metabolic Pathways that Contribute to Liver Fibrosis," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58714-5
    DOI: 10.1038/s41467-025-58714-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58714-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58714-5?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. Keren Bahar Halpern & Rom Shenhav & Orit Matcovitch-Natan & Beáta Tóth & Doron Lemze & Matan Golan & Efi E. Massasa & Shaked Baydatch & Shanie Landen & Andreas E. Moor & Alexander Brandis & Amir Gilad, 2017. "Single-cell spatial reconstruction reveals global division of labour in the mammalian liver," Nature, Nature, vol. 542(7641), pages 352-356, February.
    2. Christian Fuchsberger & Jason Flannick & Tanya M. Teslovich & Anubha Mahajan & Vineeta Agarwala & Kyle J. Gaulton & Clement Ma & Pierre Fontanillas & Loukas Moutsianas & Davis J. McCarthy & Manuel A. , 2016. "The genetic architecture of type 2 diabetes," Nature, Nature, vol. 536(7614), pages 41-47, August.
    3. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
    4. Keren Bahar Halpern & Rom Shenhav & Orit Matcovitch-Natan & Beáta Tóth & Doron Lemze & Matan Golan & Efi E. Massasa & Shaked Baydatch & Shanie Landen & Andreas E. Moor & Alexander Brandis & Amir Gilad, 2017. "Erratum: Single-cell spatial reconstruction reveals global division of labour in the mammalian liver," Nature, Nature, vol. 543(7647), pages 742-742, 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. Jingyang Qian & Xin Shao & Hudong Bao & Yin Fang & Wenbo Guo & Chengyu Li & Anyao Li & Hua Hua & Xiaohui Fan, 2025. "Identification and characterization of cell niches in tissue from spatial omics data at single-cell resolution," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    2. Franziska Hildebrandt & Alma Andersson & Sami Saarenpää & Ludvig Larsson & Noémi Van Hul & Sachie Kanatani & Jan Masek & Ewa Ellis & Antonio Barragan & Annelie Mollbrink & Emma R. Andersson & Joakim L, 2021. "Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    3. Agnieska Brazovskaja & Tomás Gomes & Rene Holtackers & Philipp Wahle & Christiane Körner & Zhisong He & Theresa Schaffer & Julian Connor Eckel & René Hänsel & Malgorzata Santel & Makiko Seimiya & Timm, 2024. "Cell atlas of the regenerating human liver after portal vein embolization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Inmaculada Ruz-Maldonado & John T. Gonzalez & Hanming Zhang & Jonathan Sun & Alicia Bort & Inamul Kabir & Richard G. Kibbey & Yajaira Suárez & Daniel M. Greif & Carlos Fernández-Hernando, 2024. "Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    5. Sun Woo Sophie Kang & Rory P. Cunningham & Colin B. Miller & Lauryn A. Brown & Constance M. Cultraro & Adam Harned & Kedar Narayan & Jonathan Hernandez & Lisa M. Jenkins & Alexei Lobanov & Maggie Cam , 2024. "A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Tomaz Martini & Cédric Gobet & Andrea Salati & Jérôme Blanc & Aart Mookhoek & Michael Reinehr & Graham Knott & Jessica Sordet-Dessimoz & Felix Naef, 2024. "A sexually dimorphic hepatic cycle of periportal VLDL generation and subsequent pericentral VLDLR-mediated re-uptake," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Delaram Pouyabahar & Tallulah Andrews & Gary D. Bader, 2025. "Interpretable single-cell factor decomposition using sciRED," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    9. Zhiyuan Yuan & Yisi Li & Minglei Shi & Fan Yang & Juntao Gao & Jianhua Yao & Michael Q. Zhang, 2022. "SOTIP is a versatile method for microenvironment modeling with spatial omics data," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    10. Zoe Piran & Mor Nitzan, 2024. "SiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Ankit Agrawal & Stefan Thomann & Sukanya Basu & Dominic Grün, 2024. "NiCo identifies extrinsic drivers of cell state modulation by niche covariation analysis," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    12. Jie Fang & Shivendra Singh & Changde Cheng & Sivaraman Natarajan & Heather Sheppard & Ahmed Abu-Zaid & Adam D. Durbin & Ha Won Lee & Qiong Wu & Jacob Steele & Jon P. Connelly & Hongjian Jin & Wenan Ch, 2023. "Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    13. Jingyang Qian & Jie Liao & Ziqi Liu & Ying Chi & Yin Fang & Yanrong Zheng & Xin Shao & Bingqi Liu & Yongjin Cui & Wenbo Guo & Yining Hu & Hudong Bao & Penghui Yang & Qian Chen & Mingxiao Li & Bing Zha, 2023. "Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Thomas A. Kluiver & Yuyan Lu & Stephanie A. Schubert & Lianne J. Kraaier & Femke Ringnalda & Philip Lijnzaad & Jeff DeMartino & Wouter L. Megchelenbrink & Vicky Amo-Addae & Selma Eising & Flavia W. Fa, 2024. "Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    15. Manuel Neumann & Xiaocai Xu & Cezary Smaczniak & Julia Schumacher & Wenhao Yan & Nils Blüthgen & Thomas Greb & Henrik Jönsson & Jan Traas & Kerstin Kaufmann & Jose M. Muino, 2022. "A 3D gene expression atlas of the floral meristem based on spatial reconstruction of single nucleus RNA sequencing data," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    16. Brianna R. Watson & Biplab Paul & Raza Ur Rahman & Liat Amir-Zilberstein & Åsa Segerstolpe & Eliana T. Epstein & Shane Murphy & Ludwig Geistlinger & Tyrone Lee & Angela Shih & Jacques Deguine & Ramnik, 2025. "Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    17. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Kristina Handler & Karsten Bach & Costanza Borrelli & Salvatore Piscuoglio & Xenia Ficht & Ilhan E. Acar & Andreas E. Moor, 2023. "Fragment-sequencing unveils local tissue microenvironments at single-cell resolution," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    19. Yuan Guan & Annika Enejder & Meiyue Wang & Zhuoqing Fang & Lu Cui & Shih-Yu Chen & Jingxiao Wang & Yalun Tan & Manhong Wu & Xinyu Chen & Patrik K. Johansson & Issra Osman & Koshi Kunimoto & Pierre Rus, 2021. "A human multi-lineage hepatic organoid model for liver fibrosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    20. Francesca Lazzeri-Barcelo & Nuria Oliva-Vilarnau & Marion Baniol & Barbara Leibiger & Olaf Bergmann & Volker M. Lauschke & Ingo B. Leibiger & Noah Moruzzi & Per-Olof Berggren, 2024. "Intraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function," Nature Communications, Nature, vol. 15(1), pages 1-14, 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:16:y:2025:i:1:d:10.1038_s41467-025-58714-5. 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.