CoChat
Sign Up
Cited by 63Liver physiology and pathologyNuclear Receptors and SignalingDevelopmental Biology and Gene Regulation

Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

Open access
Dubois, Vanessa, Staels, Bart, Lefebvre, Philippe, Verzi, Michael, Eeckhoute, Jérôme·2020·Cells
DOI 10.3390/cells9102185PMC PMC7600215
Open this paper in CoChat — free accountOpen PDF

Abstract

Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we present robust evidence pointing to HNF4 as a master regulator of cellular differentiation during development and a safekeeper of acquired cell identity in adult organs. Importantly, we discuss that transient loss of HNF4 may represent a protective mechanism upon acute organ injury, while prolonged impairment of HNF4 activities could contribute to organ dysfunction. In this context, we describe in detail mechanisms involved in the pathophysiological control of cell identity by HNF4, including how HNF4 works as part of cell-specific TF networks and how its expression/activities are disrupted in injured organs.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/cells9102185

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • HNF4A controls genes that are crucial for liver functions, primarily through binding to enhancers.

    “Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [2]

    Section 3.2 says HNF4 controls genes involved in liver-specific functions through binding to regulatory regions. It also says HNF4A binds substantially to promoters—including those of almost half the actively transcribed genes in adult liver—so the claim that it acts primarily through enhancers is not supported by this passage. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • THRB activation increased the ratio of HNF4A adult promoter P1- to embryonic promoter P2-derived isoforms.

    “In addition, THRB activation also increased the ratio of HNF4A adult promoter P1‐ to embryonic promoter P2‐derived isoforms (Fig 4H), a phenomenon known to promote hepatocyte differentiation and function (Dubois et al, 2020b).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Dubois et al, 2020b

    Section 2.1 reports a switch from P2- to P1-derived HNF4A isoforms during hepatocyte differentiation, supporting the association invoked by the citation. It does not establish that increasing the P1:P2 ratio itself promotes hepatocyte differentiation and function. The THRB-activation result is attributed to the citing paper’s Fig. 4H, not to Dubois et al. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 170

  1. [2]Morris S.A. Cell identity reprogrammed Nature 2019 575 44 45 10.1038/d41586-019-02834-8 31686043 · DOI
  2. [3]Huang M. Chen Y. Yang M. Guo A. Xu Y. Xu L. Koeffler H.P. dbCoRC: A database of core transcriptional regulatory circuitries modeled by H3K27ac ChIP-seq signals Nucleic Acids Res. 2018 46 D71 D77 10.1093/nar/gkx796 28977473 PMC5753200 · DOI
  3. [4]Hartmann A. Okawa S. Zaffaroni G. Del Sol A. SeesawPred: A Web Application for Predicting Cell-fate Determinants in Cell Differentiation Sci. Rep. 2018 8 13355 10.1038/s41598-018-31688-9 30190516 PMC6127256 · DOI
  4. [5]Zhou Q. Liu M. Xia X. Gong T. Feng J. Liu W. Liu Y. Zhen B. Wang Y. Ding C. A mouse tissue transcription factor atlas Nat. Commun. 2017 8 15089 10.1038/ncomms15089 28429721 PMC5413951 · DOI · Paper page
  5. [6]D’Alessio A.C. Fan Z.P. Wert K.J. Baranov P. Cohen M.A. Saini J.S. Cohick E. Charniga C. Dadon D. Hannett N.M. A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity Stem Cell Rep. 2015 5 763 775 10.1016/j.stemcr.2015.09.016 PMC4649293 26603904 · DOI · Paper page
  6. [7]Dubois-Chevalier J. Dubois V. Staels B. Lefebvre P. Eeckhoute J. Perspectives on the use of super-enhancers as a defining feature of cell/tissue-identity genes Epigenomics 2020 12 715 723 10.2217/epi-2019-0290 32396464 · DOI
  7. [8]Sladek F.M. Zhong W.M. Lai E. Darnell J.E.J. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily Genes Dev. 1990 4 2353 2365 10.1101/gad.4.12b.2353 2279702 · DOI · Paper page
  8. [9]Chartier F.L. Bossu J.P. Laudet V. Fruchart J.C. Laine B. Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver Gene 1994 147 269 272 10.1016/0378-1119(94)90079-5 7926813 · DOI
  9. [10]Evans R.M. Mangelsdorf D.J. Nuclear Receptors, RXR, and the Big Bang Cell 2014 157 255 266 10.1016/j.cell.2014.03.012 24679540 PMC4029515 · DOI · Paper page
  10. [11]Petrescu A.D. Hertz R. Bar-Tana J. Schroeder F. Kier A.B. Ligand specificity and conformational dependence of the hepatic nuclear factor-4alpha (HNF-4alpha) J. Biol. Chem. 2002 277 23988 23999 10.1074/jbc.M201241200 11940586 · DOI
  11. [12]Hertz R. Magenheim J. Berman I. Bar-Tana J. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha Nature 1998 392 512 516 10.1038/33185 9548258 · DOI
  12. [13]Bogan A.A. Dallas-Yang Q. Ruse M.D. Jr. Maeda Y. Jiang G. Nepomuceno L. Scanlan T.S. Cohen F.E. Sladek F.M. Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha J. Mol. Biol. 2000 302 831 851 10.1006/jmbi.2000.4099 10993727 · DOI
  13. [14]Dhe-Paganon S. Duda K. Iwamoto M. Chi Y.I. Shoelson S.E. Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand J. Biol. Chem. 2002 277 37973 37976 10.1074/jbc.C200420200 12193589 · DOI
  14. [15]Wisely G.B. A.B. M. Davis R.G. Thornquest A.D. Jr. Johnson R. Spitzer T. Sefler A. Shearer B. Moore J.T. Miller A.B. Hepatocyte Nuclear Factor 4 Is a Transcription Factor that Constitutively Binds Fatty Acids Structure 2002 10 1225 1234 10.1016/S0969-2126(02)00829-8 12220494 · DOI · Paper page
  15. [16]Duda K. Chi Y.I. Shoelson S.E. Structural basis for HNF-4alpha activation by ligand and coactivator binding J. Biol. Chem. 2004 279 23311 23316 10.1074/jbc.M400864200 14982928 · DOI
  16. [18]Yuan X. Ta T.C. Lin M. Evans J.R. Dong Y. Bolotin E. Sherman M.A. Forman B.M. Sladek F.M. Identification of an endogenous ligand bound to a native orphan nuclear receptor PLoS ONE 2009 4 e5609 10.1371/journal.pone.0005609 19440305 PMC2680617 · DOI
  17. [19]Holzer G. Markov G.V. Laudet V. Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model? Curr. Top. Dev. Biol. 2017 125 1 38 10.1016/bs.ctdb.2017.02.003 28527568 · DOI
  18. [20]Hwang-Verslues W.W. Sladek F.M. HNF4alpha--role in drug metabolism and potential drug target? Curr. Opin. Pharm. 2010 10 698 705 10.1016/j.coph.2010.08.010 PMC2981672 20833107 · DOI
  19. [21]Le Guevel R. Oger F. Lecorgne A. Dudasova Z. Chevance S. Bondon A. Barath P. Simonneaux G. Salbert G. Identification of small molecule regulators of the nuclear receptor HNF4alpha based on naphthofuran scaffolds Bioorg. Med. Chem. 2009 17 7021 7030 10.1016/j.bmc.2009.07.079 19729315 · DOI
  20. [22]Drewes T. Senkel S. Holewa B. Ryffel G.U. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes Mol. Cell Biol. 1996 16 925 931 10.1128/MCB.16.3.925 8622695 PMC231074 · DOI
  21. [23]Plengvidhya N. Antonellis A. Wogan L.T. Poleev A. Borgschulze M. Warram J.H. Ryffel G.U. Krolewski A.S. Doria A. Hepatocyte nuclear factor-4gamma: cDNA sequence, gene organization, and mutation screening in early-onset autosomal-dominant type 2 diabetes Diabetes 1999 48 2099 2102 10.2337/diabetes.48.10.2099 10512380 · DOI
  22. [24]Ko H.L. Zhuo Z. Ren E.C. HNF4alpha Combinatorial Isoform Heterodimers Activate Distinct Gene Targets that Differ from Their Corresponding Homodimers Cell Rep. 2019 26 2549 2557 10.1016/j.celrep.2019.02.033 30840880 · DOI
  23. [25]Sasaki S. Urabe M. Maeda T. Suzuki J. Irie R. Suzuki M. Tomaru Y. Sakaguchi M. Gonzalez F.J. Inoue Y. Induction of Hepatic Metabolic Functions by a Novel Variant of Hepatocyte Nuclear Factor 4gamma Mol. Cell Biol. 2018 38 e00213 e00218 10.1128/MCB.00213-18 30224520 PMC6275183 · DOI
  24. [26]Lambert E. Babeu J.-P. Simoneau J. Raisch J. Lavergne L. Lévesque D. Jolibois E. Avino M. Scott M.S. Boudreau F. Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions Mol. Cell Proteom. 2020 10.1074/mcp.RA119.001909 PMC7196586 32123031 · DOI
  25. [27]Jiang G. Nepomuceno L. Hopkins K. Sladek F.M. Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors Mol. Cell Biol. 1995 15 5131 5143 10.1128/MCB.15.9.5131 7651430 PMC230760 · DOI
  26. [28]Thomas H. Jaschkowitz K. Bulman M. Frayling T.M. Mitchell S.M. Roosen S. Lingott-Frieg A. Tack C.J. Ellard S. Ryffel G.U. A distant upstream promoter of the HNF-4α gene connects the transcription factors involved in maturity-onset diabetes of the young Hum. Mol. Genet. 2001 10 2089 2097 10.1093/hmg/10.19.2089 11590126 · DOI
  27. [29]Huang J. Levitsky L.L. Rhoads D.B. Novel P2 promoter-derived HNF4alpha isoforms with different N-terminus generated by alternate exon insertion Exp. Cell Res. 2009 315 1200 1211 10.1016/j.yexcr.2009.01.004 19353766 · DOI
  28. [30]Eeckhoute J. Moerman E. Bouckenooghe T. Lukoviak B. Pattou F. Formstecher P. Kerr-Conte J. Vandewalle B. Laine B. Hepatocyte nuclear factor 4 alpha isoforms originated from the P1 promoter are expressed in human pancreatic beta-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms Endocrinology 2003 144 1686 1694 10.1210/en.2002-0024 12697672 · DOI
  29. [31]Briancon N. Weiss M.C. In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping EMBO J. 2006 25 1253 1262 10.1038/sj.emboj.7601021 16498401 PMC1422155 · DOI
  30. [32]Chellappa K. Deol P. Evans J.R. Vuong L.M. Chen G. Briancon N. Bolotin E. Lytle C. Nair M.G. Sladek F.M. Opposing roles of nuclear receptor HNF4alpha isoforms in colitis and colitis-associated colon cancer eLife 2016 5 10.7554/eLife.10903 PMC4907689 27166517 · DOI
  31. [33]Ancey P.B. Ecsedi S. Lambert M.P. Talukdar F.R. Cros M.P. Glaise D. Narvaez D.M. Chauvet V. Herceg Z. Corlu A. TET-Catalyzed 5-Hydroxymethylation Precedes HNF4A Promoter Choice during Differentiation of Bipotent Liver Progenitors Stem Cell Rep. 2017 9 264 278 10.1016/j.stemcr.2017.05.023 28648900 PMC5511103 · DOI
  32. [34]Nakhei H. Lingott A. Lemm I. Ryffel G.U. An alternative splice variant of the tissue specific transcription factor HNF4alpha predominates in undifferentiated murine cell types Nucleic Acids Res. 1998 26 497 504 10.1093/nar/26.2.497 9421506 PMC147295 · DOI
  33. [35]Da L. Cao T. Sun X. Jin S. Di X. Huang X. Yang X. Carmichael G.G. Taylor H.S. Diano S. Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4alpha fetal isoform Nat. Commun. 2020 11 342 10.1038/s41467-019-14185-z 31953394 PMC6969024 · DOI
  34. [36]Lee D.H. Park J.O. Kim T.S. Kim S.K. Kim T.H. Kim M.C. Park G.S. Kim J.H. Kuninaka S. Olson E.N. LATS-YAP/TAZ controls lineage specification by regulating TGFbeta signaling and Hnf4alpha expression during liver development Nat. Commun. 2016 7 11961 10.1038/ncomms11961 27358050 PMC4931324 · DOI · Paper page
  35. [37]Gerard C. Tys J. Lemaigre F.P. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells Semin. Cell Dev. Biol 2017 66 43 50 10.1016/j.semcdb.2016.12.003 27979774 · DOI
  36. [38]Manmadhan S. Ehmer U. Hippo Signaling in the Liver–A Long and Ever-Expanding Story Front. Cell Dev. Biol. 2019 7 33 10.3389/fcell.2019.00033 30931304 PMC6423448 · DOI
  37. [39]Sun P. Zhang G. Su X. Jin C. Yu B. Yu X. Lv Z. Ma H. Zhang M. Wei W. Maintenance of Primary Hepatocyte Functions In Vitro by Inhibiting Mechanical Tension-Induced YAP Activation Cell Rep. 2019 29 3212 3222 10.1016/j.celrep.2019.10.128 31801084 · DOI · Paper page
  38. [40]Lu H. Crosstalk of HNF4alpha with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids Acta Pharm. Sin. B 2016 6 393 408 10.1016/j.apsb.2016.07.003 27709008 PMC5045537 · DOI
  39. [41]Zhou W. Hannoun Z. Jaffray E. Medine C.N. Black J.R. Greenhough S. Zhu L. Ross J.A. Forbes S. Wilmut I. SUMOylation of HNF4alpha regulates protein stability and hepatocyte function J. Cell Sci. 2012 125 3630 3635 10.1242/jcs.102889 22505616 PMC3445325 · DOI
  40. [42]Veto B. Bojcsuk D. Bacquet C. Kiss J. Sipeki S. Martin L. Buday L. Balint B.L. Aranyi T. The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2 PLoS ONE 2017 12 e0172020 10.1371/journal.pone.0172020 28196117 PMC5308853 · DOI
  41. [44]Dell H. Hadzopoulou-Cladaras M. CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression J. Biol. Chem. 1999 274 9013 9021 10.1074/jbc.274.13.9013 10085149 · DOI
  42. [45]Sladek F.M. Ruse M.D. Jr. Nepomuceno L. Huang S.M. Stallcup M.R. Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4alpha1 Mol. Cell Biol. 1999 19 6509 6522 10.1128/MCB.19.10.6509 10490591 PMC84621 · DOI
  43. [46]Eeckhoute J. Formstecher P. Laine B. Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4a (HNF4a) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator Mol. Endocrinol. 2001 15 1200 1210 11435618
  44. [47]Ruse M.D. Privalsky M.L. Sladek F.M. Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4 1: Modulation by the F Domain Mol. Cell. Biol. 2002 22 1626 1638 10.1128/MCB.22.6.1626-1638.2002 11865043 PMC135595 · DOI · Paper page
  45. [48]Torres-Padilla M.E. Weiss M.C. Effects of interactions of hepatocyte nuclear factor 4alpha isoforms with coactivators and corepressors are promoter-specific FEBS Lett. 2003 539 19 23 10.1016/S0014-5793(03)00174-1 12650919 · DOI
  46. [49]Battistelli C. Sabarese G. Santangelo L. Montaldo C. Gonzalez F.J. Tripodi M. Cicchini C. The lncRNA HOTAIR transcription is controlled by HNF4alpha-induced chromatin topology modulation Cell Death Differ. 2019 26 890 901 10.1038/s41418-018-0170-z 30154449 PMC6461983 · DOI
  47. [50]Nguyen H.C.B. Adlanmerini M. Hauck A.K. Lazar M.A. Dichotomous engagement of HDAC3 activity governs inflammatory responses Nature 2020 10.1038/s41586-020-2576-2 PMC7725280 32760002 · DOI · Paper page
  48. [52]Torres-Padilla M.E. Sladek F.M. Weiss M.C. Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4alpha Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes J. Biol. Chem. 2002 277 44677 44687 10.1074/jbc.M207545200 12205093 · DOI
  49. [53]Costa R.H. Grayson D.R. Darnell J.J.E. Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes Mol. Cell Biol. 1989 9 1415 1425 10.1128/MCB.9.4.1415 2786140 PMC362558 · DOI
  50. [54]Lau H.H. Ng N.H.J. Loo L.S.W. Jasmen J.B. Teo A.K.K. The molecular functions of hepatocyte nuclear factors–In and beyond the liver J. Hepatol. 2018 68 1033 1048 10.1016/j.jhep.2017.11.026 29175243 · DOI · Paper page
  51. [55]Taraviras S. Mantamadiotis T. Dong-Si T. Mincheva A. Lichter P. Drewes T. Ryffel G.U. Monaghan A.P. Schüt G.Z. Primary Structure, Chromosomal Mapping, Expression and Transcriptional Activity of Murine Hepatocyte Nuclear Factor 4gamma Biochim. Biophys. Acta 2000 1490 21 32 10.1016/S0167-4781(99)00232-8 10786614 · DOI
  52. [56]Watt A.J. Garrison W.D. Duncan S.A. HNF4: A central regulator of hepatocyte differentiation and function Hepatology 2003 37 1249 1253 10.1053/jhep.2003.50273 12774000 · DOI · Paper page
  53. [57]Chen L. Toke N.H. Luo S. Vasoya R.P. Aita R. Parthasarathy A. Tsai Y.H. Spence J.R. Verzi M.P. HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine Development 2019 146 10.1242/dev.179432 PMC6803367 31345929 · DOI
  54. [58]Chen L. Toke N.H. Luo S. Vasoya R.P. Fullem R.L. Parthasarathy A. Perekatt A.O. Verzi M.P. A reinforcing HNF4-SMAD4 feed-forward module stabilizes enterocyte identity Nat. Genet. 2019 10.1038/s41588-019-0384-0 PMC6650150 30988513 · DOI
  55. [59]Cattin A.L. Le Beyec J. Barreau F. Saint-Just S. Houllier A. Gonzalez F.J. Robine S. Pincon-Raymond M. Cardot P. Lacasa M. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium Mol. Cell Biol 2009 29 6294 6308 10.1128/MCB.00939-09 19805521 PMC2786690 · DOI
  56. [60]Marable S.S. Chung E. Adam M. Potter S.S. Park J.S. Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome Jci. Insight 2018 3 10.1172/jci.insight.97497 PMC6124415 30046000 · DOI
  57. [61]Li J. Ning G. Duncan S.A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha Genes Dev. 2000 14 464 474 10691738 PMC316377
  58. [62]Battle M.A. Konopka G. Parviz F. Gaggl A.L. Yang C. Sladek F.M. Duncan S.A. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver Proc. Natl. Acad. Sci. USA 2006 103 8419 8424 10.1073/pnas.0600246103 16714383 PMC1482507 · DOI · Paper page
  59. [63]Bolotin E. Liao H. Ta T.C. Yang C. Hwang-Verslues W. Evans J.R. Jiang T. Sladek F.M. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays Hepatology 2010 51 642 653 10.1002/hep.23357 20054869 PMC3581146 · DOI
  60. [65]Wu H. Reizel T. Wang Y.J. Lapiro J.L. Kren B.T. Schug J. Rao S. Morgan A. Herman A. Shekels L.L. A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver Proc. Natl. Acad. Sci. USA 2020 10.1073/pnas.2002898117 32631996 PMC7382236 · DOI
  61. [66]Montenegro-Miranda P.S. van der Meer J.H.M. Jones C. Meisner S. Vermeulen J.L.M. Koster J. Wildenberg M.E. Heijmans J. Boudreau F. Ribeiro A. A Novel Organoid Model of Damage and Repair Identifies HNF4α as a Critical Regulator of Intestinal Epithelial Regeneration Cell Mol. Gastroenterol. Hepatol. 2020 10 209 223 10.1016/j.jcmgh.2020.02.007 32145468 PMC7301200 · DOI
  62. [67]Walesky C. Gunewardena S. Terwilliger E.F. Edwards G. Borude P. Apte U. Hepatocyte-specific deletion of hepatocyte nuclear factor-4alpha in adult mice results in increased hepatocyte proliferation Am. J. Physiol. Gastrointest. Liver Physiol. 2013 304 G26 G37 10.1152/ajpgi.00064.2012 23104559 PMC3543634 · DOI
  63. [68]Huck I. Gunewardena S. Espanol-Suner R. Willenbring H. Apte U. Hepatocyte Nuclear Factor 4 Alpha Activation Is Essential for Termination of Liver Regeneration in Mice Hepatology 2019 70 666 681 10.1002/hep.30405 30520062 PMC6551324 · DOI
  64. [69]Dubois V. Gheeraert C. Vankrunkelsven W. Dubois-Chevalier J. Dehondt H. Bobowski-Gerard M. Vinod M. Zummo F.P. Güiza F. Ploton M. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver Mol. Syst. Biol. 2020 16 e9156 10.15252/msb.20199156 32407006 PMC7224309 · DOI · Paper page
  65. [70]Hayhurst G.P. Lee Y.H. Lambert G. Ward J.M. Gonzalez F.J. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis Mol. Cell Biol. 2001 21 1393 1403 10.1128/MCB.21.4.1393-1403.2001 11158324 PMC99591 · DOI · Paper page
  66. [71]Inoue Y. Peters L.L. Yim S.H. Inoue J. Gonzalez F.J. Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression J. Mol. Med. 2006 84 334 344 10.1007/s00109-005-0013-5 16389552 · DOI
  67. [72]Nakamori D. Akamine H. Takayama K. Sakurai F. Mizuguchi H. Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction Sci. Rep. 2017 7 16675 10.1038/s41598-017-16856-7 29192290 PMC5709502 · DOI · Paper page
  68. [73]DeLaForest A. Di Furio F. Jing R. Ludwig-Kubinski A. Twaroski K. Urick A. Pulakanti K. Rao S. Duncan S.A. HNF4A Regulates the Formation of Hepatic Progenitor Cells from Human iPSC-Derived Endoderm by Facilitating Efficient Recruitment of RNA Pol II Genes 2018 10 21 10.3390/genes10010021 30597922 PMC6356828 · DOI
  69. [74]Huang P. Zhang L. Gao Y. He Z. Yao D. Wu Z. Cen J. Chen X. Liu C. Hu Y. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes Cell Stem Cell 2014 14 370 384 10.1016/j.stem.2014.01.003 24582927 · DOI · Paper page
  70. [75]Babeu J.P. Darsigny M. Lussier C.R. Boudreau F. Hepatocyte nuclear factor 4alpha contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation Am. J. Physiol. Gastrointest. Liver Physiol. 2009 297 G124 G134 10.1152/ajpgi.90690.2008 19389805 · DOI
  71. [76]Urakami T. Maturity-onset diabetes of the young (MODY): Current perspectives on diagnosis and treatment Diabetes Metab. Syndr. Obes. 2019 12 1047 1056 10.2147/DMSO.S179793 31360071 PMC6625604 · DOI
  72. [77]Ryffel G.U. Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: Functional and pathological consequences J. Mol. Endocrinol. 2001 27 11 29 10.1677/jme.0.0270011 11463573 · DOI
  73. [79]Lehto M. Bitzén P.O. Isomaa B. Wipemo C. Wessman Y. Forsblom C. Tuomi T. Taskinen M.R. Groop L. Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism Diabetes 1999 48 423 425 10.2337/diabetes.48.2.423 10334325 · DOI
  74. [80]Pearson E.R. Pruhova S. Tack C.J. Johansen A. Castleden H.A. Lumb P.J. Wierzbicki A.S. Clark P.M. Lebl J. Pedersen O. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection Diabetologia 2005 48 878 885 10.1007/s00125-005-1738-y 15830177 · DOI
  75. [81]Shih D.Q. Dansky H.M. Fleisher M. Assmann G. Fajans S.S. Stoffel M. Genotype/phenotype relationships in HNF-4alpha/MODY1: Haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels Diabetes 2000 49 832 837 10.2337/diabetes.49.5.832 10905494 · DOI
  76. [82]Marchesin V. Perez-Marti A. Le Meur G. Pichler R. Grand K. Klootwijk E.D. Kesselheim A. Kleta R. Lienkamp S. Simons M. Molecular Basis for Autosomal-Dominant Renal Fanconi Syndrome Caused by HNF4A Cell Rep. 2019 29 4407 4421 10.1016/j.celrep.2019.11.066 31875549 PMC6941224 · DOI
  77. [83]Meddens C.A. Harakalova M. van den Dungen N.A. Foroughi Asl H. Hijma H.J. Cuppen E.P. Bjorkegren J.L. Asselbergs F.W. Nieuwenhuis E.E. Mokry M. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease Genome Biol. 2016 17 247 10.1186/s13059-016-1100-3 27903283 PMC5131449 · DOI
  78. [84]Chahar S. Gandhi V. Yu S. Desai K. Cowper-Sal-lari R. Kim Y. Perekatt A.O. Kumar N. Thackray J.K. Musolf A. Chromatin profiling reveals regulatory network shifts and a protective role for hepatocyte nuclear factor 4alpha during colitis Mol. Cell Biol. 2014 34 3291 3304 10.1128/MCB.00349-14 24980432 PMC4135557 · DOI
  79. [85]Marcil V. Sinnett D. Seidman E. Boudreau F. Gendron F.P. Beaulieu J.F. Menard D. Lambert M. Bitton A. Sanchez R. Association between genetic variants in the HNF4A gene and childhood-onset Crohn’s disease Genes Immun. 2012 13 556 565 10.1038/gene.2012.37 22914433 PMC4931920 · DOI
  80. [86]Babeu J.P. Boudreau F. Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks World J. Gastroenterol. 2014 20 22 30 10.3748/wjg.v20.i1.22 24415854 PMC3886012 · DOI
  81. [87]Barrett J.C. Lee J.C. Lees C.W. Prescott N.J. Anderson C.A. Phillips A. Wesley E. Parnell K. Zhang H. Drummond H. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region Nat. Genet. 2009 41 1330 1334 10.1038/ng.483 19915572 PMC2812019 · DOI
  82. [88]Martinez-Jimenez C.P. Kyrmizi I. Cardot P. Gonzalez F.J. Talianidis I. Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism Mol. Cell Biol. 2010 30 565 577 10.1128/MCB.00927-09 19933841 PMC2812226 · DOI
  83. [89]Armour S.M. Remsberg J.R. Damle M. Sidoli S. Ho W.Y. Li Z. Garcia B.A. Lazar M.A. An HDAC3-PROX1 corepressor module acts on HNF4alpha to control hepatic triglycerides Nat. Commun. 2017 8 549 10.1038/s41467-017-00772-5 28916805 PMC5601916 · DOI · Paper page
  84. [90]Joo M.S. Koo J.H. Kim T.H. Kim Y.S. Kim S.G. LRH1-driven transcription factor circuitry for hepatocyte identity: Super-enhancer cistromic analysis EBioMedicine 2019 40 488 503 10.1016/j.ebiom.2018.12.056 30638865 PMC6413675 · DOI
  85. [91]Boyer L.A. Lee T.I. Cole M.F. Johnstone S.E. Levine S.S. Zucker J.P. Guenther M.G. Kumar R.M. Murray H.L. Jenner R.G. Core transcriptional regulatory circuitry in human embryonic stem cells Cell 2005 122 947 956 10.1016/j.cell.2005.08.020 16153702 PMC3006442 · DOI · Paper page
  86. [92]Kyrmizi I. Hatzis P. Katrakili N. Tronche F. Gonzalez F.J. Talianidis I. Plasticity and expanding complexity of the hepatic transcription factor network during liver development Genes Dev. 2006 20 2293 2305 10.1101/gad.390906 16912278 PMC1553211 · DOI · Paper page
  87. [93]Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes Cell 2013 153 307 319 10.1016/j.cell.2013.03.035 23582322 PMC3653129 · DOI · Paper page
  88. [94]Odom D.T. Zizlsperger N. Gordon D.B. Bell G.W. Rinaldi N.J. Murray H.L. Volkert T.L. Schreiber J. Rolfe P.A. Gifford D.K. Control of pancreas and liver gene expression by HNF transcription factors Science 2004 303 1378 1381 10.1126/science.1089769 14988562 PMC3012624 · DOI
  89. [95]San Roman A.K. Aronson B.E. Krasinski S.D. Shivdasani R.A. Verzi M.P. Transcription factors GATA4 and HNF4A control distinct aspects of intestinal homeostasis in conjunction with transcription factor CDX2 J. Biol. Chem. 2015 290 1850 1860 10.1074/jbc.M114.620211 25488664 PMC4340426 · DOI
  90. [96]Morris S.A. Cahan P. Li H. Zhao A.M. San Roman A.K. Shivdasani R.A. Collins J.J. Daley G.Q. Dissecting engineered cell types and enhancing cell fate conversion via CellNet Cell 2014 158 889 902 10.1016/j.cell.2014.07.021 25126792 PMC4291075 · DOI
  91. [97]Verzi M.P. Shin H. He H.H. Sulahian R. Meyer C.A. Montgomery R.K. Fleet J.C. Brown M. Liu X.S. Shivdasani R.A. Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2 Dev. Cell 2010 19 713 726 10.1016/j.devcel.2010.10.006 21074721 PMC3001591 · DOI
  92. [100]Ballester B. Medina-Rivera A. Schmidt D. Gonzalez-Porta M. Carlucci M. Chen X. Chessman K. Faure A.J. Funnell A.P. Goncalves A. Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways eLife 2014 3 e02626 10.7554/eLife.02626 25279814 PMC4359374 · DOI · Paper page
  93. [102]Natarajan A. Yardimci G.G. Sheffield N.C. Crawford G.E. Ohler U. Predicting cell-type-specific gene expression from regions of open chromatin Genome Res. 2012 22 1711 1722 10.1101/gr.135129.111 22955983 PMC3431488 · DOI
  94. [103]Dubois-Chevalier J. Dubois V. Dehondt H. Mazrooei P. Mazuy C. Sérandour A.A. Gheeraert C. Guillaume P. Baugé E. Derudas B. The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions Genome Res. 2017 27 985 996 10.1101/gr.217075.116 28400425 PMC5453331 · DOI · Paper page
  95. [104]Alpern D. Langer D. Ballester B. Le Gras S. Romier C. Mengus G. Davidson I. TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation eLife 2014 3 e03613 10.7554/eLife.03613 25209997 PMC4359380 · DOI
  96. [105]Chen L. Vasoya R.P. Toke N.H. Parthasarathy A. Luo S. Chiles E. Flores J. Gao N. Bonder E.M. Su X. HNF4 Regulates Fatty Acid Oxidation and Is Required for Renewal of Intestinal Stem Cells in Mice Gastroenterology 2020 158 985 999 10.1053/j.gastro.2019.11.031 31759926 PMC7062567 · DOI
  97. [106]Qu M. Duffy T. Hirota T. Kay S.A. Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks Proc. Natl. Acad. Sci. USA 2018 10.1073/pnas.1816411115 PMC6310821 30530698 · DOI
  98. [109]Palierne G. Fabre A. Solinhac R. Le Péron C. Avner S. Lenfant F. Fontaine C. Salbert G. Flouriot G. Arnal J.F. Changes in Gene Expression and Estrogen Receptor Cistrome in Mouse Liver Upon Acute E2 Treatment Mol. Endocrinol. 2016 30 709 732 10.1210/me.2015-1311 27164166 PMC5426578 · DOI
  99. [110]Stadhouders R. Filion G.J. Graf T. Transcription factors and 3D genome conformation in cell-fate decisions Nature 2019 569 345 354 10.1038/s41586-019-1182-7 31092938 · DOI
  100. [111]Stefflova K. Thybert D. Wilson M.D. Streeter I. Aleksic J. Karagianni P. Brazma A. Adams D.J. Talianidis I. Marioni J.C. Cooperativity and rapid evolution of cobound transcription factors in closely related mammals Cell 2013 154 530 540 10.1016/j.cell.2013.07.007 23911320 PMC3732390 · DOI
  101. [112]Dubois-Chevalier J. Mazrooei P. Lupien M. Staels B. Lefebvre P. Eeckhoute J. Organizing combinatorial transcription factor recruitment at cis-regulatory modules Transcription 2017 10.1080/21541264.2017.1394424 29105538 PMC6104691 · DOI
  102. [113]Xia B. Zhao D. Wang G. Zhang M. Lv J. Tomoiaga A.S. Li Y. Wang X. Meng S. Cooke J.P. Machine learning uncovers cell identity regulator by histone code Nat. Commun. 2020 11 2696 10.1038/s41467-020-16539-4 32483223 PMC7264183 · DOI
  103. [114]Schmidt D. Wilson M.D. Ballester B. Schwalie P.C. Brown G.D. Marshall A. Kutter C. Watt S. Martinez-Jimenez C.P. Mackay S. Five-vertebrate ChIP-seq Reveals the Evolutionary Dynamics of Transcription Factor Binding Science 2010 328 1036 1040 10.1126/science.1186176 20378774 PMC3008766 · DOI · Paper page
  104. [115]Ramaker R.C. Hardigan A.A. Goh S.T. Partridge E.C. Wold B. Cooper S.J. Myers R.M. Dissecting the regulatory activity and sequence content of loci with exceptional numbers of transcription factor associations Genome Res. 2020 10.1101/gr.260463.119 PMC7397867 32616518 · DOI
  105. [116]Reiter F. Wienerroither S. Stark A. Combinatorial function of transcription factors and cofactors Curr. Opin. Genet. Dev. 2017 43 73 81 10.1016/j.gde.2016.12.007 28110180 · DOI
  106. [117]Zaret K.S. Regulatory phases of early liver development: Paradigms of organogenesis Nat. Rev. Genet. 2002 3 499 512 10.1038/nrg837 12094228 · DOI
  107. [119]Gao N. White P. Kaestner K.H. Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2 Dev. Cell 2009 16 588 599 10.1016/j.devcel.2009.02.010 19386267 PMC2673200 · DOI
  108. [120]Karagianni P. Moulos P. Schmidt D. Odom D.T. Talianidis I. Bookmarking by Non-pioneer Transcription Factors during Liver Development Establishes Competence for Future Gene Activation Cell Rep. 2020 30 1319 1328 10.1016/j.celrep.2020.01.006 32023452 PMC7003066 · DOI
  109. [122]Qin Y. Grimm S.A. Roberts J.D. Chrysovergis K. Wade P.A. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet Nat. Commun. 2020 11 962 10.1038/s41467-020-14796-x 32075973 PMC7031266 · DOI
  110. [123]Qin Y. Roberts J.D. Grimm S.A. Lih F.B. Deterding L.J. Li R. Chrysovergis K. Wade P.A. An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression Genome Biol. 2018 19 7 10.1186/s13059-018-1389-1 29361968 PMC5782396 · DOI
  111. [124]Davison J.M. Lickwar C.R. Song L. Breton G. Crawford G.E. Rawls J.F. Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha Genome Res. 2017 27 1195 1206 10.1101/gr.220111.116 28385711 PMC5495071 · DOI
  112. [125]Wang A.W. Wang Y.J. Zahm A.M. Morgan A.R. Wangensteen K.J. Kaestner K.H. The dynamic chromatin architecture of the regenerating liver Cell Mol. Gastroenterol. Hepatol. 2019 10.1016/j.jcmgh.2019.09.006 PMC6909351 31629814 · DOI
  113. [126]Ahn S.H. Shah Y.M. Inoue J. Morimura K. Kim I. Yim S. Lambert G. Kurotani R. Nagashima K. Gonzalez F.J. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease Inflamm. Bowel. Dis. 2008 14 908 920 10.1002/ibd.20413 18338782 PMC2435391 · DOI
  114. [127]Wilflingseder J. Willi M. Lee H.K. Olauson H. Jankowski J. Ichimura T. Erben R. Valerius M.T. Hennighausen L. Bonventre J.V. Enhancer and super-enhancer dynamics in repair after ischemic acute kidney injury Nat. Commun. 2020 11 3383 10.1038/s41467-020-17205-5 32636391 PMC7341735 · DOI
  115. [128]Nikolaidou-Neokosmidou V. Zannis V.I. Kardassis D. Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor kappaB pathway Biochem. J. 2006 398 439 450 10.1042/BJ20060169 16771709 PMC1559460 · DOI
  116. [129]Simo R. Barbosa-Desongles A. Saez-Lopez C. Lecube A. Hernandez C. Selva D.M. Molecular Mechanism of TNFalpha-Induced Down-Regulation of SHBG Expression Mol. Endocrinol. 2012 26 438 446 10.1210/me.2011-1321 22301786 PMC5417125 · DOI
  117. [130]Arensdorf A.M. Dezwaan McCabe D. Kaufman R.J. Rutkowski D.T. Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network Front. Genet. 2013 4 188 10.3389/fgene.2013.00188 24069029 PMC3781334 · DOI
  118. [131]Chikka M.R. McCabe D.D. Tyra H.M. Rutkowski D.T. C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver J. Biol. Chem. 2013 288 4405 4415 10.1074/jbc.M112.432344 23281479 PMC3567690 · DOI
  119. [132]DeZwaan-McCabe D. Sheldon R.D. Gorecki M.C. Guo D.F. Gansemer E.R. Kaufman R.J. Rahmouni K. Gillum M.P. Taylor E.B. Teesch L.M. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis Cell Rep. 2017 19 1794 1806 10.1016/j.celrep.2017.05.020 28564599 PMC5520660 · DOI
  120. [133]Chellappa K. Jankova L. Schnabl J.M. Pan S. Brelivet Y. Fung C.L. Chan C. Dent O.F. Clarke S.J. Robertson G.R. Src tyrosine kinase phosphorylation of nuclear receptor HNF4alpha correlates with isoform-specific loss of HNF4alpha in human colon cancer Proc. Natl. Acad. Sci. USA 2012 109 2302 2307 10.1073/pnas.1106799109 22308320 PMC3289305 · DOI
  121. [134]Hasnain S.Z. Lourie R. Das I. Chen A.C. McGuckin M.A. The interplay between endoplasmic reticulum stress and inflammation Immunol. Cell Biol. 2012 90 260 270 10.1038/icb.2011.112 22249202 PMC7165805 · DOI
  122. [135]Silveira M.A.D. Bilodeau S. Defining the Transcriptional Ecosystem Mol. Cell 2018 72 920 924 10.1016/j.molcel.2018.11.022 30576654 · DOI
  123. [136]Ayres J.S. The Biology of Physiological Health Cell 2020 181 250 269 10.1016/j.cell.2020.03.036 32302569 PMC7409982 · DOI
  124. [137]Luebke-Wheeler J. Zhang K. Battle M. Si-Tayeb K. Garrison W. Chhinder S. Li J. Kaufman R.J. Duncan S.A. Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H Hepatology 2008 48 1242 1250 10.1002/hep.22439 18704925 PMC2717709 · DOI
  125. [138]Moore B.D. Jin R.U. Lo H. Jung M. Wang H. Battle M.A. Wollheim C.B. Urano F. Mills J.C. Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4A) Is Vital to Beta-cell Function J. Biol. Chem. 2016 291 6146 6157 10.1074/jbc.M115.685750 26792861 PMC4813565 · DOI
  126. [139]Gjuvsland A.B. Plahte E. Omholt S.W. Threshold-dominated regulation hides genetic variation in gene expression networks BMC Syst. Biol. 2007 1 57 10.1186/1752-0509-1-57 18062810 PMC2238762 · DOI
  127. [140]Félix M.A. Barkoulas M. Pervasive robustness in biological systems Nat. Rev. Genet. 2015 16 483 496 10.1038/nrg3949 26184598 · DOI
  128. [141]Wang W. Yao L.J. Shen W. Ding K. Shi P.M. Chen F. He J. Ding J. Zhang X. Xie W.F. FOXA2 alleviates CCl(4)-induced liver fibrosis by protecting hepatocytes in mice Sci. Rep. 2017 7 15532 10.1038/s41598-017-15831-6 29138513 PMC5686201 · DOI
  129. [143]Bueno-Hernández N. Sánchez-Muñoz F. Barreto-Zuñiga R. Dominguez-López A. Yamamoto-Furusho J.K. 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 E91 10.1002/ibd.21753 21618351 · DOI
  130. [144]Xu J. Xu Y. Li Y. Jadhav K. You M. Yin L. Zhang Y. Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury Sci. Rep. 2016 6 24277 10.1038/srep24277 27075303 PMC4831009 · DOI
  131. [145]Xu Y. Zalzala M. Xu J. Li Y. Yin L. Zhang Y. A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism Nat. Commun. 2015 6 7466 10.1038/ncomms8466 26100857 PMC4479415 · DOI
  132. [146]Desai S.S. Tung J.C. Zhou V.X. Grenert J.P. Malato Y. Rezvani M. Espanol-Suner R. Willenbring H. Weaver V.M. Chang T.T. Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha Hepatology 2016 64 261 275 10.1002/hep.28450 26755329 PMC5224931 · DOI · Paper page
  133. [147]Berasain C. Avila M.A. Regulation of hepatocyte identity and quiescence Cell Mol. Life Sci. 2015 72 3831 3851 10.1007/s00018-015-1970-7 26089250 PMC11114060 · DOI
  134. [148]Guzman-Lepe J. Cervantes-Alvarez E. Collin de l’Hortet A. Wang Y. Mars W.M. Oda Y. Bekki Y. Shimokawa M. Wang H. Yoshizumi T. Liver-enriched transcription factor expression relates to chronic hepatic failure in humans Hepatol. Commun. 2018 2 582 594 10.1002/hep4.1172 29761173 PMC5944584 · DOI
  135. [149]Sandovici I. Smith N.H. Nitert M.D. Ackers-Johnson M. Uribe-Lewis S. Ito Y. Jones R.H. Marquez V.E. Cairns W. Tadayyon M. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets Proc. Natl. Acad. Sci. USA 2011 108 5449 5454 10.1073/pnas.1019007108 21385945 PMC3069181 · DOI · Paper page
  136. [151]Cai W.Y. Lin L.Y. Hao H. Zhang S.M. Ma F. Hong X.X. Zhang H. Liu Q.F. Ye G.D. Sun G.B. Yes-associated protein/TEA domain family member and hepatocyte nuclear factor 4-alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice Hepatology 2017 65 1206 1221 10.1002/hep.28911 27809333 · DOI
  137. [152]Ning B.F. Ding J. Yin C. Zhong W. Wu K. Zeng X. Yang W. Chen Y.X. Zhang J.P. Zhang X. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma Cancer Res. 2010 70 7640 7651 10.1158/0008-5472.CAN-10-0824 20876809 · DOI
  138. [153]Pan J. Silva T.C. Gull N. Yang Q. Plummer J.T. Chen S. Daigo K. Hamakubo T. Gery S. Ding L.W. Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas Cancer Res. 2020 80 2722 2736 10.1158/0008-5472.CAN-20-0390 32332020 · DOI
  139. [154]Kitao A. Matsui O. Yoneda N. Kozaka K. Kobayashi S. Koda W. Minami T. Inoue D. Yoshida K. Yamashita T. Gadoxetic acid-enhanced magnetic resonance imaging reflects co-activation of β-catenin and hepatocyte nuclear factor 4α in hepatocellular carcinoma Hepatol. Res. 2018 48 205 216 10.1111/hepr.12911 28488786 · DOI
  140. [155]Walesky C. Edwards G. Borude P. Gunewardena S. O’Neil M. Yoo B. Apte U. Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents Hepatology 2013 57 2480 2490 10.1002/hep.26251 23315968 PMC3669646 · DOI
  141. [156]Fekry B. Ribas-Latre A. Baumgartner C. Mohamed A.M.T. Kolonin M.G. Sladek F.M. Younes M. Eckel-Mahan K.L. HNF4alpha-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma Cancer Res. 2019 79 5860 5873 10.1158/0008-5472.CAN-19-1277 31575546 PMC6881553 · DOI
  142. [157]Saha S.K. Parachoniak C.A. Ghanta K.S. Fitamant J. Ross K.N. Najem M.S. Gurumurthy S. Akbay E.A. Sia D. Cornella H. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer Nature 2014 513 110 114 10.1038/nature13441 25043045 PMC4499230 · DOI
  143. [158]Thiery J.P. Acloque H. Huang R.Y. Nieto M.A. Epithelial-mesenchymal transitions in development and disease Cell 2009 139 871 890 10.1016/j.cell.2009.11.007 19945376 · DOI · Paper page
  144. [159]Santangelo L. Marchetti A. Cicchini C. Conigliaro A. Conti B. Mancone C. Bonzo J.A. Gonzalez F.J. Alonzi T. Amicone L. The stable repression of mesenchymal program is required for hepatocyte identity: A novel role for hepatocyte nuclear factor 4alpha Hepatology 2011 53 2063 2074 10.1002/hep.24280 21384409 PMC6624426 · DOI
  145. [160]Huang Q. Pu M. Zhao G. Dai B. Bian Z. Tang H. Chen C. Liu W. Qu X. Shen L. Tg737 regulates epithelial-mesenchymal transition and cancer stem cell properties via a negative feedback circuit between Snail and HNF4α during liver stem cell malignant transformation Cancer Lett. 2017 402 52 60 10.1016/j.canlet.2017.05.005 28536011 · DOI
  146. [161]Morimoto A. Kannari M. Tsuchida Y. Sasaki S. Saito C. Matsuta T. Maeda T. Akiyama M. Nakamura T. Sakaguchi M. An HNF4alpha-microRNA-194/192 signaling axis maintains hepatic cell function J. Biol. Chem. 2017 292 10574 10585 10.1074/jbc.M117.785592 28465351 PMC5481564 · DOI
  147. [162]Cicchini C. de Nonno V. Battistelli C. Cozzolino A.M. De Santis Puzzonia M. Ciafre S.A. Brocker C. Gonzalez F.J. Amicone L. Tripodi M. Epigenetic control of EMT/MET dynamics: HNF4alpha impacts DNMT3s through miRs-29 Biochim. Biophys. Acta 2015 1849 919 929 10.1016/j.bbagrm.2015.05.005 26003733 PMC6319628 · DOI
  148. [163]Chang H. Liu Y. Xue M. Liu H. Du S. Zhang L. Wang P. Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition Nucleic Acids Res. 2016 44 2514 2527 10.1093/nar/gkw126 26926107 PMC4824118 · DOI
  149. [164]Hwang-Verslues W.W. Sladek F.M. Nuclear receptor hepatocyte nuclear factor 4alpha1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter Mol. Endocrinol. 2008 22 78 90 10.1210/me.2007-0298 17885207 PMC2194635 · DOI
  150. [165]Jiang C.F. Wen L.Z. Yin C. Xu W.P. Shi B. Zhang X. Xie W.F. Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4α on hepatocellular carcinoma Oncotarget 2016 7 27408 27421 10.18632/oncotarget.8478 27050273 PMC5053659 · DOI
  151. [166]Hatziapostolou M. Polytarchou C. Aggelidou E. Drakaki A. Poultsides G.A. Jaeger S.A. Ogata H. Karin M. Struhl K. Hadzopoulou-Cladaras M. An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis Cell 2011 147 1233 1247 10.1016/j.cell.2011.10.043 22153071 PMC3251960 · DOI
  152. [167]Perugorria M.J. Castillo J. Latasa M.U. Goñi S. Segura V. Sangro B. Prieto J. Avila M.A. Berasain C. Wilms’ tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy Cancer Res. 2009 69 1358 1367 10.1158/0008-5472.CAN-08-2545 19190340 · DOI
  153. [168]Maeda Y. Hwang-Verslues W.W. Wei G. Fukazawa T. Durbin M.L. Owen L.B. Liu X. Sladek F.M. Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene Biochem. J. 2006 400 303 313 10.1042/BJ20060614 16895524 PMC1652821 · DOI
  154. [169]Hatzis P. Kyrmizi I. Talianidis I. Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nuclear factor 4alpha expression Mol. Cell Biol. 2006 26 7017 7029 10.1128/MCB.00297-06 16980607 PMC1592892 · DOI
  155. [170]De Lucas S. Lopez-Alcorocho J.M. Bartolome J. Carreno V. Nitric oxide and TGF-beta1 inhibit HNF-4alpha function in HEPG2 cells Biochem. Biophys. Res. Commun. 2004 321 688 694 10.1016/j.bbrc.2004.07.025 15358161 · DOI
  156. [171]Li T. Chiang J.Y. A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene Gastroenterology 2007 133 1660 1669 10.1053/j.gastro.2007.08.042 17920062 · DOI
  157. [172]Cozzolino A.M. Alonzi T. Santangelo L. Mancone C. Conti B. Steindler C. Musone M. Cicchini C. Tripodi M. Marchetti A. TGFbeta overrides HNF4alpha tumor suppressing activity through GSK3beta inactivation: Implication for hepatocellular carcinoma gene therapy J. Hepatol. 2013 58 65 72 10.1016/j.jhep.2012.08.023 22960426 · DOI
  158. [173]Sun W. Ding J. Wu K. Ning B.F. Wen W. Sun H.Y. Han T. Huang L. Dong L.W. Yang W. Gankyrin-mediated dedifferentiation facilitates the tumorigenicity of rat hepatocytes and hepatoma cells Hepatology 2011 54 1259 1272 10.1002/hep.24530 21735473 · DOI
  159. [174]Fitamant J. Kottakis F. Benhamouche S. Tian H.S. Chuvin N. Parachoniak C.A. Nagle J.M. Perera R.M. Lapouge M. Deshpande V. YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression Cell Rep. 2015 10.1016/j.celrep.2015.02.027 PMC4565791 25772357 · DOI · Paper page
  160. [175]Noce V. Battistelli C. Cozzolino A.M. Consalvi V. Cicchini C. Strippoli R. Tripodi M. Marchetti A. Amicone L. YAP integrates the regulatory Snail/HNF4alpha circuitry controlling epithelial/hepatocyte differentiation Cell Death Dis. 2019 10 768 10.1038/s41419-019-2000-8 31601778 PMC6787001 · DOI
  161. [176]Yeh M.M. Bosch D.E. Daoud S.S. Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases World J. Gastroenterol. 2019 25 4074 4091 10.3748/wjg.v25.i30.4074 31435165 PMC6700705 · DOI
  162. [177]Guo S. Lu H. Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α J. Cell. Biochem. 2018 120 519 532 10.1002/jcb.27407 30191603 PMC7745837 · DOI
  163. [178]Vuong L.M. Chellappa K. Dhahbi J.M. Deans J.R. Fang B. Bolotin E. Titova N.V. Hoverter N.P. Spindler S.R. Waterman M.L. Differential Effects of Hepatocyte Nuclear Factor 4alpha Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells Mol. Cell Biol. 2015 35 3471 3490 10.1128/MCB.00030-15 26240283 PMC4573706 · DOI
  164. [179]Tanaka T. Jiang S. Hotta H. Takano K. Iwanari H. Sumi K. Daigo K. Ohashi R. Sugai M. Ikegame C. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer J. Pathol. 2006 208 662 672 10.1002/path.1928 16400631 · DOI
  165. [180]Argemi J. Latasa M.U. Atkinson S.R. Blokhin I.O. Massey V. Gue J.P. Cabezas J. Lozano J.J. Van Booven D. Bell A. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis Nat. Commun. 2019 10 10.1038/s41467-019-11004-3 PMC6635373 31311938 · DOI
  166. [182]Wang J. Qin R. Ma Y. Wu H. Peters H. Tyska M. Shaheen N.J. Chen X. Differential gene expression in normal esophagus and Barrett’s esophagus J. Gastroenterol. 2009 44 897 911 10.1007/s00535-009-0082-2 19468668 PMC3811010 · DOI
  167. [183]Schwartz B. Algamas-Dimantov A. Hertz R. Nataf J. Kerman A. Peri I. Bar-Tana J. Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha Int. J. Cancer 2009 124 1081 1089 10.1002/ijc.24041 19048623 · DOI
  168. [184]Colleypriest B.J. Burke Z.D. Griffiths L.P. Chen Y. Yu W.Y. Jover R. Bock M. Biddlestone L. Quinlan J.M. Ward S.G. Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium Differentiation 2017 93 39 49 10.1016/j.diff.2016.11.001 27875772 PMC5293356 · DOI
  169. [185]Rogerson C. Britton E. Withey S. Hanley N. Ang Y.S. Sharrocks A.D. Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state Genome Res. 2019 29 723 736 10.1101/gr.243345.118 30962179 PMC6499311 · DOI
  170. [186]Shukla S. Cyrta J. Murphy D.A. Walczak E.G. Ran L. Agrawal P. Xie Y. Chen Y. Wang S. Zhan Y. Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance Cancer Cell 2017 10.1016/j.ccell.2017.10.008 PMC5728174 29153843 · DOI

Cited by

Sorted by citations

Authors
Dubois, V., Staels, B., Lefebvre, P., Verzi, M., & Eeckhoute, J.
Affiliations
  • KU Leuven (BE)
  • Inserm (FR)
  • U1011-EGID, Institut Pasteur de Lille, CHU Lille, Inserm, Univ. Lille, F-59000 Lille, France
  • Rutgers, The State University of New Jersey (US)
Corresponding author
  • Dubois, Vanessa
  • Eeckhoute, Jérôme
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-09-28
Volume
9
Issue
10
Pages
2185
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells9102185
PMC
PMC7600215
OpenAlex
W3089150323
Cited by
63
References
16
Citations by year
2026: 4 · 2025: 11 · 2024: 8 · 2023: 14 · 2022: 16 · 2021: 9 · 2020: 1
FWCI
1.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Agence Nationale de la Recherche (ANR‐10‐LABX‐46)
  • Fondation pour la Recherche Médicale (DEQ20150331724)
  • European Research Council (694717)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
HNF4, nuclear receptors, transcription factors, cell identity, cell differentiation, organogenesis, organ damage, organ dysfunction, liver, gastrointestinal tract
MeSH terms
Binding Sites, DNA-Binding Proteins, Humans, Liver, Promoter Regions, Genetic, Transcription Factors, Organogenesis, Hepatocyte Nuclear Factor 4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review