Hepatocyte Nuclear Factor (HNFa)

HNF4A gene

Hepatocyte Nuclear Factor (HNFa)

From NCBI Gene:

The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes.

This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms.

[provided by RefSeq, Apr 2012]

From UniProt:

Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).

Covered on Genetics Home Reference:

  • Congenital hyperinsulinism

From NCBI Gene:

  • Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
  • Diabetes mellitus type 2
  • Maturity-onset diabetes of the young, type 1

From UniProt:

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (FRTS4): A disease characterized by Fanconi syndrome associated with a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes.

Fanconi syndrome is a proximal tubulopathy resulting in generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia.

Some FRTS4 patients have nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia. [MIM:616026]

Diabetes mellitus, non-insulin-dependent (NIDDM): A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin.

Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia.

The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. [MIM:125853]

Maturity-onset diabetes of the young 1 (MODY1): A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. [MIM:125850]

Cytogenetic Location: 20q13.12, which is the long (q) arm of chromosome 20 at position 13.12

Molecular Location: base pairs 44,355,699 to 44,434,596 on chromosome 20 (Homo sapiens Updated Annotation Release 109.20191205, GRCh38.p13) (NCBI)

  • FRTS4
  • HNF4
  • HNF4a7
  • HNF4a8
  • HNF4a9
  • HNF4alpha
  • MODY
  • MODY1
  • NR2A1
  • NR2A21
  • TCF
  • TCF14

Source: https://ghr.nlm.nih.gov/gene/HNF4A

TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha

Hepatocyte Nuclear Factor (HNFa)

The TRIB1 locus has been linked to both cardiovascular disease and hepatic steatosis. Recent efforts have revealed TRIB1 to be a major regulator of liver function, largely, but not exclusively, via CEBPA degradation.

We recently uncovered a functional interaction between TRIB1 and HNF4A, another key regulator of hepatic function, whose molecular underpinnings remained to be clarified. Here we have extended these findings. In hepatoma models, HNF4A levels were found to depend on TRIB1, independently of its impact on CEBPA.

Using a reporter assay model, MTTP reporter activity, which depends on HNF4A, positively correlated with TRIB1 levels. Confocal microscopy demonstrated partial colocalization of TRIB1 and HNF4A. Using overexpressed proteins we demonstrate that TRIB1 and HNF4A can form complexes in vivo.

Mapping of the interaction interfaces identified two distinct regions within TRIB1 which associated with the N-terminal region of HNF4A. Lastly, the TRIB1-HNF4A interaction resisted competition with a CEPBA-derived peptide, suggesting different binding modalities.

Together these findings establish that TRIB1 is required for HNF4A function. This regulatory axis represents a novel CEBPA-independent aspect of TRIB1 function predicted to play an important role in liver physiology.

The TRIBBLES proteins form a family of 3 mammalian proteins (TRIB1, 2 and 3) sharing ~30% overall identity, characterized by the presence of a relatively well-conserved core kinase- domain and divergent N and C-termini.

Un bona fide kinases, the TRIBBLES exhibit no detectable kinase activity (with the exception of TRIB2) as a result of mutations at key catalytic residues1, 2. Rather, they act as molecular adaptors by regulating other kinases and/or targets thereof.

Over the years numerous roles, pathological and physiological roles have been ascribed to the TRIBBLES3, 4. For TRIB1 specifically, research has focused on leukemia and more recently, lipid and lipoprotein metabolism.

Genome-wide Association Studies (GWAS) have identified a locus proximal (~30 kb) to TRIB1 that associates with increased plasma triglycerides and a predisposition for cardiovascular disease (CAD)5. Importantly, TRIB1 has also been linked to hepatic steatosis6.

In a previous work we observed an inverse correlation between the top CAD risk single nucleotide polymorphism (SNP) and TRIB1 expression levels in whole blood on the one hand and circulating lipids on the other hand, suggesting that TRIB1 may play a role in reducing hepatic triglyceride synthesis and secretion in humans7.

Whole animal models have uncovered roles for TRIB1 in both lipid and glucose metabolism8. Of the numerous proximal targets of TRIB1 identified over the years, there is a consensus on the ability of TRIB1 to promote CEBPA degradation9. Recently Bauer et al. have demonstrated a close functional relationship between these proteins in mouse liver10.

More specifically, liver-specific TRIB1 deficiency could be partially rescued by CEBPA knock-out hinting that a major function of TRIB1 in the liver is to regulate CEBPA.

Importantly, while circulating lipid levels could be rescued by CEBPA knock-out, hepatic lipid accumulation (steatosis) could not, indicating that TRIB1 has roles transcending CEBPA regulation.

We recently identified a functional interaction between HNF4A and TRIB1 11. TRIB1 suppression resulted in impaired HNF4A function inferred from reduced HNF4A, HNF1B and increased SNAI1 transcripts in primary hepatocytes.

In HepG2 cells, a widely used hepatic cell model, HNF4A protein levels were reduced as a result of TRIB1 suppression while HNF4A suppression increased TRIB1 transcript abundance.

HNF4A is a highly conserved member (NR2A1) of the nuclear receptor family and is unique among the nuclear receptor superfamily in its ability to bind DNA exclusively as a homodimer and activate transcription in the absence of exogenous ligand12.

HNF4A plays a pivotal metabolic role by regulating the expression of liver and intestinal genes13, 14. HNF4A is essential for TG, cholesterol homeostasis and bile acid metabolism and helps regulate the expression of several key lipoprotein regulators including APOC3 and MTTP 15,16,17,18,19.

In addition, loss of HNF4A perturbs the function of key regulators of the mesenchymal-to-epithelial transition (EMT) and is associated with the development of hepatic steatosis and hepatocellular carcinoma20, 21.

Interestingly HNF4A and CEBPA co-localize extensively on chromatin and loss of Hnf4a reduces the ability of Cebpa to bind DNA and vice versa22. In this work the interplay between TRIB1 and HNF4A is explored and a general requirement for the TRIBBLES in sustaining HNF4A protein levels is demonstrated. In addition a protein-protein interaction between HNF4A and TRIB1 is described and mapped.

In our previous work we observed that TRIB1 suppression led to reduced HNF4A expression in both HepG2 cells and human primary hepatocytes11. Interestingly while TRIB1 suppression is associated with reduced HNF4A transcript levels in primary hepatocytes, no such change is obvious in HepG2 (Suppl Fig.

 1), suggesting that TRIB1 may utilize transcriptional and non-transcriptional mechanisms to regulate HNF4A. To examine how prevalent this relationship was, we examined the impact of TRIB1 silencing in another widely studied human hepatoma cell line, HuH-7 cells where TRIB1 suppression led to reduced HNF4A protein (Fig. 1A).

This change was associated with a 26% reduction in HNF4A transcript (74 ± 18% of control (n = 6, p = 0.02). Thus HuH-7 cells, in contrast to HepG2 cells, seem to have retained some capacity to sustain HNF4A transcript levels via TRIB1.

Yet as HNF4A protein levels in HuH-7 and HepG2 cells exhibit similar and pronounced (~50% reduction and11) sensitivities to TRIB1 silencing, this suggests that transcriptional impacts may not single-handedly account for lower HNF4A protein expression in HuH-7 cells.

Figure 1

HNF4A expression depends on all the TRIBBLES, with a greater contribution of TRIB1. (A,B) HuH-7 cells were treated for 72 h with the indicated siRNAs and analyzed for protein content by Western blotting.

Quantifications of HNF4A (relative to TUBB and then normalized to the NT value) are shown under the blot (means of 3 biological replicates ± S.D).

Changes in HNF4A transcript were tested for statistical significance using one-way ANOVA followed by between group comparisons using Tukey’s post-hoc test. TRIB1 vs TRIB2/TRIB3: p 

Source: https://www.nature.com/articles/s41598-017-05768-1

F1000Prime Recommended Article: Hepatocyte nuclear factor 4 alpha activation is essential for termination of liver regeneration in mice

Hepatocyte Nuclear Factor (HNFa)

  • Registration is free and only takes a moment, or subscribe for unlimited access.

    Register

    Already registered with F1000Prime?

    Sign In

    Recommend F1000Prime to your librarian or information manager to request an extended free trial for all users at your institution.

    Recommend to your librarian

  • Hepatocyte nuclear factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration (LR) is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels, accompanied with decreased target gene expression, within 1 hour after two-thirds partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO [knockout]) in mice resulted in 100% mortality post-PH, despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated that HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c-Myc and cyclin D1 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno-associated virus serotype 8 (AAV8)-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression, and improved survival of HNF4α-KO mice post-PH. Conclusion: In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of LR. These results indicate the role of HNF4α in LR and have implications for therapy of liver failure.

    © 2018 by the American Association for the Study of Liver Diseases.

    This work was supported by:

    • Grant ID: P30 GM118247
    • Grant ID: R56DK112768A
    • Grant ID: R01DK98414
    • Grant ID: R56 DK112768
    • Grant ID: T32ES007079-34
    • Grant ID: R56 DK112768
    • Grant ID: R01 DK098414
    • Grant ID: P20 RR021940-03
    • Grant ID: P30 DK026743
    • Grant ID: R01 DK098414
    • Grant ID: T32 ES007079
    • Grant ID: P20 RR021940
    • Grant ID: P30 DK026743

    More Less keyboard_arrow_down

  • Source: https://f1000.com/prime/734569984

    Online Mendelian Inheritance in Man (OMIM)

    Hepatocyte Nuclear Factor (HNFa)

    1. Aguilar-Salinas, C. A., Reyes-Rodriguez, E., Ordonez-Sanchez, M. L., Torres, M. A., Ramirez-Jimenez, S., Dominguez-Lopez, A., Martinez-Francois, J. R., Velasco-Perez, M. L., Alpizar, M., Garcia-Garcia, E., Gomez-Perez, F., Rull, J., Tusie-Luna, M.

      T. Early-onset type 2 diabetes: metabolic and genetic characterization in the Mexican population. J. Clin. Endocr. Metab. 86: 220-226, 2001. [PubMed: 11232004] [Full Text: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.86.1.

      7134]

    2. Argyrokastritis, A., Kamakari, S., Kapsetaki, M., Kritis, A., Talianidis, I., Moschonas, N. K. Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17. Hum. Genet. 99: 233-236, 1997. [PubMed: 9048927] [Full Text: https://dx.doi.org/10.1007/s004390050345]

    3. Avraham, K. B., Prezioso, V. R., Chen, W. S., Lai, E., Sladek, F. M., Zhong, W., Darnell, J. E., Jr., Jenkins, N. A., Copeland, N. G.

      Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3-alpha, HNF3-beta, HNF-3-gamma, and HNF-4. Genomics 13: 264-268, 1992.

      [PubMed: 1612587] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/0888-7543(92)90241-J]

    4. Barrio, R., Bellanne-Chantelot, C., Moreno, J. C., Morel, V., Calle, H., Alonso, M., Mustieles, C. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J. Clin. Endocr. Metab. 87: 2532-2539, 2002. [PubMed: 12050210] [Full Text: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.87.6.8530]

    5. Battle, M. A., Konopka, G., Parviz, F., Gaggl, A. L., Yang, C., Sladek, F. M., Duncan, S. A. Hepatocyte nuclear factor 4-alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc. Nat. Acad. Sci. 103: 8419-8424, 2006. [PubMed: 16714383] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16714383]

    6. Chandra, V., Huang, P., Potluri, N., Wu, D., Kim, Y., Rastinejad, F. Multidomain integration in the structure of the HNF-4-alpha nuclear receptor complex. Nature 495: 394-398, 2013. [PubMed: 23485969] [Full Text: https://doi.org/10.1038/nature11966]

    7. Chartier, F. L., Bossu, J.-P., Laudet, V., Fruchart, J.-C. Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene 147: 269-272, 1994. [PubMed: 7926813] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/0378-1119(94)90079-5]

    8. 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. Nature Genet. 51: 777-785, 2019. [PubMed: 30988513] [Full Text: https://dx.doi.org/10.1038/s41588-019-0384-0]

    9. Eeckhoute, J., Formstecher, P., Laine, B.

      Maturity-onset diabetes of the young type 1 (MODY1)-associated mutations R154X and E276Q in hepatocyte nuclear factor 4-alpha (HNF4-alpha) gene impair recruitment of p300, a key transcriptional coactivator. Molec. Endocr. 15: 1200-1210, 2001. [PubMed: 11435618] [Full Text: https://academic.oup.com/mend/article-lookup/doi/10.1210/mend.15.7.0670]

    10. Fajans, S. S., Bell, G. I., Polonsky, K. S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New Eng. J. Med. 345: 971-980, 2001. [PubMed: 11575290] [Full Text: http://www.nejm.org/doi/full/10.1056/NEJMra002168?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed]

    11. Fajans, S. S. Maturity-onset diabetes of the young (MODY). Diabetes Metab. Rev. 5: 579-606, 1989. [PubMed: 2689121] [Full Text: https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0742-4221&date=1989&volume=5&issue=7&spage=579]

    12. Furuta, H., Iwasaki, N., Oda, N., Hinokio, Y., Horikawa, Y., Yamagata, K., Yano, N., Sugahiro, J., Ogata, M., Ohgawara, H., Omori, Y., Iwamoto, Y., Bell, G. I.

      Organization and partial sequence of the hepatocyte nuclear factor-4-alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes 46: 1652-1657, 1997.

      [PubMed: 9313765] [Full Text: http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=9313765]

    13. Gross, M. B. Personal Communication. Baltimore, Md. 9/30/2014.

    14. Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., Duncan, S. A., Kaestner, K. H. The MODY1 gene HNF-4-alpha regulates selected genes involved in insulin secretion. J. Clin. Invest. 115: 1006-1015, 2005. [PubMed: 15761495] [Full Text: https://doi.org/10.1172/JCI22365]

    15. Hamilton, A. J., Bingham, C., McDonald, T. J., Cook, P. R. Caswell, R. C., Weedon, M. N., Oram, R. A., Shields, B. M., Shepherd, M., Inward, C. D., Hamilton-Shield, J. P., Kohlhase, J., Ellard, S., Hattersley, A. T.

      The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a beta cell phenotype. J. Med. Genet. 51: 165-169, 2014. [PubMed: 24285859] [Full Text: http://jmg.bmj.

      com/cgi/pmidlookup?view=long&pmid=24285859]

    16. Hani, E. H., Suaud, L., Boutin, P., Chevre, J.-C., Durand, E., Philippi, A., Demenais, F., Vionnet, N., Furuta, H., Velho, G., Bell, G. I., Laine, B., Froguel, P.

      A missense mutation in hepatocyte nuclear factor-4-alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J. Clin. Invest. 101: 521-526, 1998.

      [PubMed: 9449683] [Full Text: https://doi.org/10.1172/JCI1403]

    17. Johansen, A., Ek, J., Mortensen, H. B., Pedersen, O., Hansen, T. Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. J. Clin. Endocr. Metab. 90: 4607-4614, 2005. [PubMed: 15928245] [Full Text: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2005-0196]

    18. Lausen, J., Thomas, H., Lemm, I., Bulman, M., Borgschulze, M., Lingott, A., Hattersley, A. T., Ryffel, G. U. Naturally occurring mutations in the human HNF4-alpha gene impair the function of the transcription factor to a varying degree. Nucleic Acids Res. 28: 430-437, 2000. [PubMed: 10606640] [Full Text: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/28.2.430]

    19. Li, J., Ning, G., Duncan, S. A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4-alpha. Genes Dev. 14: 464-474, 2000. [PubMed: 10691738] [Full Text: http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=10691738]

    20. Lindner, T., Gragnoli, C., Furuta, H., Cockburn, B. N., Petzold, C., Rietzsch, H., Weiss, U., Schulze, J., Bell, G. I. Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4-alpha/MODY1 gene. J. Clin. Invest. 100: 1400-1405, 1997. [PubMed: 9294105] [Full Text: https://doi.org/10.1172/JCI119660]

    21. 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 3: 97497, 2018. Note: Electronic Article. [PubMed: 30046000] [Full Text: https://doi.org/10.1172/jci.insight.97497]

    22. Moller, A. M., Dalgaard, L. T., Ambye, L., Hansen, L., Schmitz, O., Hansen, T., Pedersen, O.

      A novel Phe75fsdelT mutation in the hepatocyte nuclear factor-4-alpha gene in a Danish pedigree with maturity-onset diabetes of the young. J. Clin. Endocr. Metab. 84: 367-369, 1999.

      [PubMed: 9920109] [Full Text: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.84.1.5396]

    23. Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., Fraenkel, E. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genet. 39: 730-732, 2007. [PubMed: 17529977] [Full Text: https://dx.doi.org/10.1038/ng2047]

    24. 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., Fraenkel, E., Bell, G. I., Young, R. A.

      Control of pancreas and liver gene expression by HNF transcription factors. Science 303: 1378-1381, 2004. [PubMed: 14988562] [Full Text: http://www.sciencemag.

      org/cgi/pmidlookup?view=long&pmid=14988562]

    25. Parviz, F., Matullo, C., Garrison, W. D., Savatski, L., Adamson, J. W., Ning, G., Kaestner, K. H., Rossi, J. M., Zaret, K. S., Duncan, S. A. Hepatocyte nuclear factor 4-alpha controls the development of a hepatic epithelium and liver morphogenesis. Nature Genet. 34: 292-296, 2003. [PubMed: 12808453] [Full Text: https://dx.doi.org/10.1038/ng1175]

    26. Pearson, E. R., Boj, S. F., Steele, A. M., Barrett, T., Stals, K., Shield, J. P., Ellard, S., Ferrer, J., Hattersley, A. T. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 4: e118, 2007. Note: Electronic Article. [PubMed: 17407387] [Full Text: http://dx.plos.org/10.1371/journal.pmed.0040118]

    27. Ribeiro, A., Pastier, D., Kardassis, D., Chambaz, J., Cardot, P. Cooperative binding of upstream stimulatory factor and hepatic nuclear factor 4 drives the transcription of the human apolipoprotein A-II gene. J. Biol. Chem. 274: 1216-1225, 1999. [PubMed: 9880489] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9880489]

    28. 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., Miltiadous, O., Walesky, C., and 14 others.

      Mutant IDH inhibits HNF-4-alpha to block hepatocyte differentiation and promote biliary cancer. Nature 513: 110-114, 2014. Note: Erratum: Nature 519: 118 only, 2015. Note: Erratum: Nature 528: 152 only, 2015.

      [PubMed: 25043045] [Full Text: https://doi.org/10.1038/nature13441]

    29. 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., Talianidis, I., Flicek, P., Odom, D. T.

      Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328: 1036-1040, 2010. [PubMed: 20378774] [Full Text: http://www.sciencemag.

      org/cgi/pmidlookup?view=long&pmid=20378774]

    30. Sekiya, S., Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte- cells by defined factors. Nature 475: 390-393, 2011. [PubMed: 21716291] [Full Text: https://doi.org/10.1038/nature10263]

    31. Stanescu, D. E., Hughes, N., Kaplan, B., Stanley, C. A., De Leon, D. D. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J. Clin. Endocr. Metab. 97: E2026-E2030, 2012. Note: Electronic Article. [PubMed: 22802087] [Full Text: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2012-1356]

    32. Stoffel, M., Duncan, S. A. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4-alpha regulates expression of genes required for glucose transport and metabolism. Proc. Nat. Acad. Sci. 94: 13209-13214, 1997. [PubMed: 9371825] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9371825]

    33. Thomas, H., Jaschkowitz, K., Bulman, M., Frayling, T. M., Mitchell, S. M. S., Roosen, S., Lingott-Frieg, A., Tack, C. J., Ellard, S., Ryffel, G. U., Hattersley, A. T.

      A distant upstream promoter of the HNF-4-alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum. Molec. Genet. 10: 2089-2097, 2001.

      [PubMed: 11590126] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/10.19.2089]

    34. Tirona, R. G., Lee, W., Leake, B. F., Lan, L.-B., Cline, C. B., Lamba, V., Parviz, F., Duncan, S. A., Inoue, Y., Gonzalez, F. J., Schuetz, E. G., Kim, R. B. The orphan nuclear receptor HNF4-alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nature Med. 9: 220-224, 2003. [PubMed: 12514743] [Full Text: https://dx.doi.org/10.1038/nm815]

    35. Yamagata, K., Furuta, H., Oda, N., Kaisaki, P. J., Menzel, S., Cox, N. J., Fajans, S. S., Signorini, S., Stoffel, M., Bell, G. I. Mutations in the hepatocyte nuclear factor-4-alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384: 458-460, 1996. [PubMed: 8945471] [Full Text: https://doi.org/10.1038/384458a0]

    36. Zouali, H., Hani, E. H., Philippi, A., Vionnet, N., Beckmann, J. S., Demenais, F., Froguel, P.

      A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum. Molec. Genet.

      6: 1401-1408, 1997. [PubMed: 9285775] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/6.9.1401]

    Source: https://www.omim.org/entry/600281

    healthyincandyland.com