Multiple Roles and Regulatory Mechanisms of the Transcription Factor HNF4 in the Intestine

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2023 Aug 28

PMID 37635981

Authors

Kiranmayi Vemuri

Sarah H Radi

Frances M Sladek

Michael P Verzi

Affiliations

Soon will be listed here.

Abstract

Hepatocyte nuclear factor 4-alpha (HNF4α) drives a complex array of transcriptional programs across multiple organs. Beyond its previously documented function in the liver, HNF4α has crucial roles in the kidney, intestine, and pancreas. In the intestine, a multitude of functions have been attributed to HNF4 and its accessory transcription factors, including but not limited to, intestinal maturation, differentiation, regeneration, and stem cell renewal. Functional redundancy between HNF4α and its intestine-restricted paralog HNF4γ, and co-regulation with other transcription factors drive these functions. Dysregulated expression of HNF4 results in a wide range of disease manifestations, including the development of a chronic inflammatory state in the intestine. In this review, we focus on the multiple molecular mechanisms of HNF4 in the intestine and explore translational opportunities. We aim to introduce new perspectives in understanding intestinal genetics and the complexity of gastrointestinal disorders through the lens of HNF4 transcription factors.

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References

Barker N, van de Wetering M, Clevers H . The intestinal stem cell. Genes Dev. 2008; 22(14):1856-64. PMC: 2735277. DOI: 10.1101/gad.1674008. View

Girard R, Darsigny M, Jones C, Maloum-Rami F, Gelinas Y, Carpentier A . HNF4α is a novel regulator of intestinal glucose-dependent insulinotropic polypeptide. Sci Rep. 2019; 9(1):4200. PMC: 6414548. DOI: 10.1038/s41598-019-41061-z. View

San Roman A, Aronson B, Krasinski S, Shivdasani R, Verzi M . Transcription factors GATA4 and HNF4A control distinct aspects of intestinal homeostasis in conjunction with transcription factor CDX2. J Biol Chem. 2014; 290(3):1850-60. PMC: 4340426. DOI: 10.1074/jbc.M114.620211. View

Beinsteiner B, Billas I, Moras D . Structural insights into the HNF4 biology. Front Endocrinol (Lausanne). 2023; 14:1197063. PMC: 10315846. DOI: 10.3389/fendo.2023.1197063. View

van der Wath R, Gardiner B, Burgess A, Smith D . Cell organisation in the colonic crypt: a theoretical comparison of the pedigree and niche concepts. PLoS One. 2013; 8(9):e73204. PMC: 3771985. DOI: 10.1371/journal.pone.0073204. View

Garrison W, Battle M, Yang C, Kaestner K, Sladek F, Duncan S . Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology. 2006; 130(4):1207-20. PMC: 3581272. DOI: 10.1053/j.gastro.2006.01.003. View

Barrero M, Malik S . Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation. Mol Cell. 2006; 24(2):233-43. PMC: 1647399. DOI: 10.1016/j.molcel.2006.09.020. View

Stoffel M, Duncan S . The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A. 1997; 94(24):13209-14. PMC: 24288. DOI: 10.1073/pnas.94.24.13209. View

Ning B, Ding J, Yin C, Zhong W, Wu K, Zeng X . Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res. 2010; 70(19):7640-51. DOI: 10.1158/0008-5472.CAN-10-0824. View

10.

Schmidt D, Wilson M, Ballester B, Schwalie P, Brown G, Marshall A . Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science. 2010; 328(5981):1036-40. PMC: 3008766. DOI: 10.1126/science.1186176. View

11.

Holewa B, Zapp D, Drewes T, Senkel S, Ryffel G . HNF4beta, a new gene of the HNF4 family with distinct activation and expression profiles in oogenesis and embryogenesis of Xenopus laevis. Mol Cell Biol. 1997; 17(2):687-94. PMC: 231794. DOI: 10.1128/MCB.17.2.687. View

12.

Chellappa K, Deol P, Evans J, Vuong L, Chen G, Briancon N . Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer. Elife. 2016; 5. PMC: 4907689. DOI: 10.7554/eLife.10903. View

13.

Oshima T, Kawasaki T, Ohashi R, Hasegawa G, Jiang S, Umezu H . Downregulated P1 promoter-driven hepatocyte nuclear factor-4alpha expression in human colorectal carcinoma is a new prognostic factor against liver metastasis. Pathol Int. 2007; 57(2):82-90. DOI: 10.1111/j.1440-1827.2006.02061.x. View

14.

Beyaz S, Mana M, Roper J, Kedrin D, Saadatpour A, Hong S . High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature. 2016; 531(7592):53-8. PMC: 4846772. DOI: 10.1038/nature17173. View

15.

Bueno-Hernandez N, Sanchez-Munoz F, Barreto-Zuniga R, Dominguez-Lopez A, Yamamoto-Furusho J . Expression of HNF4γ is downregulated in patients with active ulcerative colitis (UC) compared to UC patients in remission and healthy controls. Inflamm Bowel Dis. 2011; 17(8):E91. DOI: 10.1002/ibd.21753. View

16.

Beck F, Chawengsaksophak K, Luckett J, Giblett S, Tucci J, Brown J . A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice. Dev Biol. 2003; 255(2):399-406. DOI: 10.1016/s0012-1606(02)00096-9. View

17.

Hatzis P, Talianidis I . Regulatory mechanisms controlling human hepatocyte nuclear factor 4alpha gene expression. Mol Cell Biol. 2001; 21(21):7320-30. PMC: 99906. DOI: 10.1128/MCB.21.21.7320-7330.2001. View

18.

Fang B, Mane-Padros D, Bolotin E, Jiang T, Sladek F . Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors. Nucleic Acids Res. 2012; 40(12):5343-56. PMC: 3384313. DOI: 10.1093/nar/gks190. View

19.

Stegmann A, Hansen M, Wang Y, Larsen J, Lund L, Ritie L . Metabolome, transcriptome, and bioinformatic cis-element analyses point to HNF-4 as a central regulator of gene expression during enterocyte differentiation. Physiol Genomics. 2006; 27(2):141-55. DOI: 10.1152/physiolgenomics.00314.2005. View

20.

Banerjee K, Saxena M, Kumar N, Chen L, Cavazza A, Toke N . Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development. Genes Dev. 2018; 32(21-22):1430-1442. PMC: 6217732. DOI: 10.1101/gad.318832.118. View