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At least 19 recordsLinked to original sources
PubMed1991

Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head.

By analysis of cDNA clones that cross-hybridized with a portion of the cDNA encoding the recently described rat protein hepatocyte nuclear factor 3 alpha (HNF-3 alpha, previously called HNF-3A), we now describe two additional members, HNF-3 beta and HNF-3 gamma, of this gene family. A 110-amino-acid region in the DNA-binding domain of this family is not only very highly conserved in rodents (HNF-3 alpha, -3 beta, and -3 gamma are identical in 93 of 110 amino acids in this region) but also in Drosophila where the homeotic gene fork head has 88 of the 93 residues that are identical in the three rat genes. The HNF-3 family in rodents is expressed in cells that derive from the lining of the primitive gut; some of the embryonic Drosophila cells in which fork head is expressed also give rise to gut and salivary glands. Thus, it appears that this gene family, the DNA-binding portion of which is unlike that of any previously recognized DNA-binding proteins, may contribute to differentiation of cells in internal organs in both vertebrates and invertebrates.

Amino Acid Sequence↗
PubMed1994

Hepatocyte nuclear factor-3 (HNF-3) binds to the insulin response sequence in the IGF binding protein-1 (IGFBP-1) promoter and enhances promoter function.

IGF binding protein-1 is an important short-term modulator of IGF bioavailability. Hepatic transcription of IGFBP-1 is increased by glucocorticoids and suppressed by insulin. We previously identified adjacent glucocorticoid and insulin response sequences approximately 90 bp 5' to the RNA cap site in the IGFBP-1 promoter. This insulin response sequence contains a sequence highly related (10/12 bases) to a consensus HNF-3 binding sequence. Gel shift and supershift studies confirm that this sequence binds HNF-3 alpha, beta and gamma. Co-expression of HNF-3 beta enhances IGFBP-1 promoter activity in NIH-3T3 cells. Mutation of this HNF-3 binding sequence disrupts this effect as well as the ability of glucocorticoids to stimulate and of insulin to inhibit IGFBP-1 promoter activity in H4IIE and HepG2 hepatoma cells. HNF-3 binding at this site may play an important role in the multihormonal regulation of hepatic IGFBP-1 gene expression.

3T3 Cells↗
PubMed1995

Laminin-rich extracellular matrix maintains high level of hepatocyte nuclear factor 4 in rat hepatocyte culture.

Laminin-rich extracellular matrix, EHS-gel, has been demonstrated to keep a high level of liver-specific gene expression in cultured rat hepatocytes. To obtain information about the effect of EHS-gel on liver-specific functions, gene expression of liver-enriched transcription factors in rat hepatocytes was investigated. The apolipoprotein A-I and albumin mRNA levels were higher in hepatocytes cultured on EHS-gel than in those cultured on type I collagen (TIC). The levels of mRNA for HNF-4, C/EBP alpha and C/EBP beta were also higher on EHS-gel than on TIC. The level of HNF-4 mRNA in hepatocytes on EHS-gel was almost comparable to that in liver. The HNF-3 alpha mRNA level was lower on EHS-gel than on TIC. C/EBP beta mRNA was induced by dexamethasone in both EHS-gel and TIC. The induction of C/EBP alpha and HNF-4 by dexamethasone was observed only on TIC. These data suggest that EHS-gel leads hepatocytes to keep the phenotypic expression through high expression of liver-enriched transcription factors, such as HNF-4.

Animals↗
PubMed1995

Interplay between a new HNF3 and the HNF1 transcriptional factors in the duck hepatitis B virus enhancer.

We identified a new hepatocyte nuclear factor 3 (HNF3) binding site in the DHBV enhancer. This site is close to the hepatocyte nuclear factor 1 (HNF1) binding site, responsible for most of the enhancing activity. No differences in the migrating properties were found between this new site and the two other HNF3 sites recently described in this enhancer. Factor HNF1 strongly inhibits binding of the HNF3 factor in this newly characterized site. The two factors were never detected simultaneously on the DNA fragment, even when their respective concentrations were modified. Competition persisted after enlarging by 5 and 10 nucleotides the space between the two sites. On the contrary, when the HNF3 binding site was changed into the perfect consensus site, binding of the HNF3 factor was not inhibited any longer by HNF1 and a supershift, corresponding to the binding of both factors, was observed. Thus a limited mismatching appears to modulate the interaction between transcriptional proteins and DNA and allows a second transcriptional protein to interplay with the former one.

Base Sequence↗
PubMed1992

Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4.

The genes for rat hepatocyte nuclear factors 3 and 4 (HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4) have been mapped in mouse by analysis of restriction fragment length polymorphisms in interspecific backcross mice. These hepatocyte-enriched transcription factors are positive-acting transcription factors with binding sites in regulatory regions of many genes expressed in hepatocytes. Both HNF-3 alpha, beta, and gamma and HNF-4 are also expressed in intestine. They have recently been implicated as potential participants in endodermal development from early gut cells because of their close homology to Drosophila genes, which themselves are expressed in the developing gut. Despite having similar functional roles and highly conserved DNA binding domains, the three loci from the Hnf-3 family of genes mapped to three different mouse chromosomes, suggesting that the Hnf-3 family has become widely dispersed during evolution and implying the necessity for independent activation of each member of the HNF-3 family.

Animals↗
PubMed1995

The hepatocyte nuclear factor-3/forkhead transcription regulatory family in development, inflammation, and neoplasia.

HNF-3/FKH genes are a large family of transcriptional activators. They are expressed in specific developmental and tissue patterns. Indeed, several of them are known to be essential for normal development (e.g. Dfkh and slp-1,2). Mutation within one of these genes produces mutant fruitfly embryos that are unable to survive. This family shares conserved DNA binding and transcriptional activation domains. The DNA binding domain has been crystallized, and its structure determined. Although it has resemblance to helices of homeodomains and H5 histones, it represents a new DNA binding motif, which has been called the 'winged helix,' because it contains additional interactive peptide regions called termed wings. Subtle amino acid variations in a region adjacent to the DNA recognition helix influence the recognition specificity of each HNF-3/FKH protein and therefore confer selectivity in promoter regulation. Members of this family are important in regulating the inflammatory response of the liver (the three HNF-3 genes). In addition, several members may be important in blood cell development (H3 and 5-3). Finally, two of these genes have been found to produce neoplasia (qin and FKHR). As investigation progresses, the mechanism by which these genes regulate development, inflammation and neoplasia will become more clear.

Animals↗
PubMed1991

Site-directed mutagenesis of hepatocyte nuclear factor (HNF) binding sites in the mouse transthyretin (TTR) promoter reveal synergistic interactions with its enhancer region.

The transthyretin (TTR) gene is regulated by two DNA regions which elicit hepatocyte-specific expression: a proximal promoter and distal enhancer. The TTR promoter and enhancer are composed of at least eight DNA binding sites for three different hepatocyte nuclear factors (HNF), CCAAT/enhancer binding protein (C/EBP), and AP-1/cJun. Site directed mutations within each of the HNF binding sites in the TTR promoter were introduced to evaluate their contribution to transcriptional activity in hepatoma cells. The data indicate that the strong affinity HNF-3-S binding site (-106 to -94) is absolutely required for TTR promoter activity since several mutations in this site eliminate TTR expression in the context of its enhancer. Conversion of a second weak affinity HNF3-W site (-140 to -131) in the TTR promoter to a high affinity site resulted in higher levels of expression. TTR mutations that disrupted several weak affinity sites (HNF1, HNF3-W, and HNF4) only slightly diminished expression levels in the presence of the TTR enhancer. In contrast, when we deleted the TTR enhancer from these HNF mutant constructs, TTR expression decreased to undetectable levels. This result suggests cooperation between the factors binding to the TTR promoter and enhancer regions. These results also demonstrate that the HNF3-S site alone is not sufficient to activate TTR transcription, but rather requires the participation of three cell-specific factors to elicit minimal promoter activity. The complexity of this promoter design and the requirement for a minimal number of cell-specific factors to achieve transcription allows us to propose a model which may explain the maintenance of tissue-specific expression of TTR.

Animals↗
PubMed1991

The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology.

The extracellular matrix (ECM) promotes tissue morphogenesis, cell migration, and the differentiation of a variety of cell types. However, the mechanisms by which ECM causes differentiated gene expression have been unknown. In this report, we show that culturing the hepatocyte-derived cell line H2.35 on an ECM gel changes cell morphology and selectively stimulates the transcription of a subset of liver-specific genes, including serum albumin. Transcriptional activation by ECM also occurs with transfected plasmids bearing the transcriptional enhancer of the albumin gene. ECM substrates of different composition activated the albumin enhancer only when the ECM promoted a cuboidal, differentiated cell morphology. Enhancer activation by the ECM was mediated by two liver transcription factors, HNF3 alpha and eH-TF, which appear to be regulated differently by matrix. Specifically, we found that a collagen gel substratum caused a selective increase in the factor HNF3 alpha at the levels of mRNA accumulation and DNA-binding activity in nuclear extracts, both in H2.35 cells and in the hepatoma cell line HepG2. We conclude that the ECM can stimulate cell differentiation by selectively activating transcriptional regulatory factors and that such regulation occurs coordinately with ECM-promoted changes in cell shape.

Albumins↗
PubMed1995

Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes.

The rate of transcription of the hepatic phosphoenolpyruvate carboxykinase (PEPCK) and insulin-like growth factor-binding protein 1 (IGFBP-1) genes is stimulated by glucocorticoids and inhibited by insulin. In both cases, the effect of insulin is dominant, since it suppresses both basal and glucocorticoid-stimulated PEPCK or IGFBP-1 gene transcription. Analyses of both promoters by transfection of PEPCK or IGFBP-1-chloramphenicol acetyltransferase fusion genes into rat hepatoma cells has led to the identification of insulin response sequences (IRSs) in both genes. The core IRS, T(G/A)TTTTG, is the same in both genes, but the PEPCK promoter has a single copy of this element whereas the IGFBP-1 promoter has two copies arranged as an inverted palindrome. The IGFBP-1 IRS and PEPCK IRS both bind the alpha and beta forms of hepatic nuclear factor 3 (HNF-3), although the latter does so with a sixfold-lower relative affinity. Both the PEPCK and the IGFBP-1 IRSs also function as accessory factor binding sites required for the full induction of gene transcription by glucocorticoids. A combination of transient transfection and DNA binding studies suggests that HNF-3 is the accessory factor that supports glucocorticoid-induced gene transcription. In both genes, the HNF-3 binding site overlaps the IRS core motif(s). A model in which insulin is postulated to mediate its negative effect on glucocorticoid-induced PEPCK and IGFBP-1 gene transcription indirectly by inhibiting HNF-3 action is proposed.

Animals↗
PubMed1995

Molecular analysis of the distal enhancer of the mouse alpha-fetoprotein gene.

The mouse alpha-fetoprotein (AFP) gene is transcribed at high levels in the visceral endoderm of the yolk sac and fetal liver and at much lower rates in the endoderm of the fetal gut. Expression of the gene in vivo requires the presence of at least one of three enhancers which lie in its 5' flanking region. In this report, we establish that the most distal AFP enhancer directed consistent expression of a linked AFP minigene in all three endodermal tissues in transgenic mice. The enhancer is composed of three domains, each of which is essential for full enhancer function by transient transfection assays. DNase I footprinting identified three regions of the enhancer which are protected by human hepatoma nuclear extracts, one of which corresponded to a consensus site for HNF-3 binding. Site-directed mutations in this site caused a 10-fold reduction in enhancer function by transient transfection. In transgenic mice, however, the mutation resulted in sporadic expression of the transgene, dependent on the site of integration. A similar acquisition of position-dependent sporadic expression of the transgene was observed with a mutation in a second protein binding site, despite the fact that this mutation had very little effect on enhancer function as assessed by transient transfection. These studies underscore the value of examining the functions of specific protein binding sites in vivo.

Animals↗
PubMed1991

Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells.

To investigate the regulation of genes whose expression is enriched in liver we studied expression of the albumin and transthyretin (TTR) genes in a series of rat hepatoma cell lines (FaO, C2, C2rev7, and H5) that express these genes at different rates. The level of expression of albumin and TTR was compared to the expression and DNA-binding activity of four transcription factors, HNF1/LFB1, C/EBP, HNF3, and HNF4, that are found at high concentrations in liver. We conclude that the levels of these factors are controlled both transcriptionally (HNF-3, HNF-4, and C/EBP) and post-transcriptionally (HNF-1/LFB1), and that the cellular concentration of these DNA-binding proteins helps explain the level of transcriptional activity observed for the genes they regulate.

Albumins↗
PubMed2026

Integrated molecular and immune profiling identifies FOXA1 as a complementary co-target to MUC1 for bispecific immunotherapy in breast cancer.

In breast cancer immunotherapy, Mucin 1 (MUC1) is a well-established target with promising preclinical results; however, single targeting of MUC1 has demonstrated limited efficacy in clinical trials, largely due to tumor heterogeneity, diverse glycosylation patterns, and an immunosuppressive TME. Identification of complementary co-targets enables bi-specific or dual-target immunotherapy, limiting antigen escape, improving specificity, and reducing relapse. Here, we employed a comprehensive multi-layered analytical approach to evaluate MUC1 expression, clinical relevance, and methylation status, followed by systematic screening of MUC1-correlated genes. Antigenicity prediction and protein-protein interaction analyses identified Forkhead Box A1 (FOXA1) as a potential functional partner. Expression analysis revealed concordant patterns of MUC1 and FOXA1 across breast cancer samples, while network mapping demonstrated shared interactions with adhesion-associated proteins, including CTNNB1, CTNND1, and CDH1, suggesting roles in epithelial organization and tumor progression. Further validation using gene expression datasets from Indian breast cancer cohorts confirmed consistent expression and correlation patterns, supporting reproducibility across populations. Immune profiling revealed an inverse association between MUC1-FOXA1 co-expression and immune-related gene signatures, with high co-expression linked to reduced infiltration of dendritic cells, CD4⁺ and CD8⁺ T cells, macrophages, and natural killer cells, indicative of an immunosuppressive microenvironment. Negative correlations with MHC Class I genes further suggested impaired antigen presentation. Epitope prediction identified high-affinity peptides from both targets with strong MHC Class I binding potential. Collectively, these findings support the associated role of MUC1 and FOXA1 as dual immunotherapeutic targets in breast cancer.

Hepatocyte Nuclear Factor 3-alpha↗
PubMed2026

3D epigenomic remodelling mediated by Foxa1 drives gemcitabine resistance in pancreatic cancer.

Gemcitabine remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet the emergence of resistance constitutes a major clinical challenge with poorly understood epigenomic mechanisms. Here, we identified the pioneer transcription factor Foxa1 as a master regulator of gemcitabine resistance through multi-omics analysis. Mechanistically, Foxa1 drives widespread super-enhancer (SE) reprogramming and 3D genome remodelling in resistant cells, which coordinately activates the expression of key resistance genes, notably Rrm1 and Cdadc1. This is accompanied by increased chromatin accessibility, elevated H3K27ac enrichment at SEs, and enhanced Foxa1 binding at regulatory elements. Moreover, post-translational stabilization of Foxa1 via USP7-mediated deubiquitination sustains this epigenomic program. Genetic ablation of Foxa1 or specific SE regions near Rrm1 resensitizes resistant cells to gemcitabine. Building upon this mechanism, we demonstrate that bromodomain and extraterminal (BET) inhibitors, which disrupt SE function, potently reverse resistance. Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC.

Hepatocyte Nuclear Factor 3-alpha↗
PubMed1992

Developmentally regulated Drosophila gene family encoding the fork head domain.

We have isolated seven Drosophila genes by means of low-stringency hybridization to a DNA probe containing the coding sequence for the protein domain shared by the rodent hepatocyte-enriched nuclear transcription factor HNF3A (alpha) and the product of the Drosophila region-specific homeotic gene fork head (fkh). The previously unreported genes encode a 110-amino acid conserved sequence, which we call the fork head (fkh) domain. Two of these fkh-domain-encoding genes ("FD genes") map to the sloppy paired locus (slp), which exerts segmentation gene function. The expression patterns of the other FD genes suggest that their protein products are likely to be involved in gut formation, mesoderm specification, and some specific aspects of neural development. The FD gene products presumably represent a family of transcription factors that, like the previously identified DNA-binding proteins, contribute to early developmental decisions in cell fates during embryogenesis.

Amino Acid Sequence↗
PubMed1990

HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally.

Hepatocyte-specific gene expression requires the interaction of many proteins with multiple binding sites in the regulatory regions. HNF-3 is a site found to be important in the maximal hepatocyte-specific expression of several genes. We find that liver nuclear extracts contain three major binding activities for this site, which we call HNF-3A, HNF-3B, and HNF-3C. Purification from rat liver nuclear extracts of HNF-3A and HNF-3C reveals that each activity corresponds to a distinct polypeptide, as determined by SDS-PAGE. Peptide sequence derived from the most abundant species, HNF-3A, was used for synthesizing probes with which to isolate a cDNA clone of this protein. The encoded protein contains 466 amino acids (48.7 kD) and has binding properties identical to those of the purified protein. A 160-amino-acid region that does not resemble the binding domain of any known transcription factor is essential for DNA binding. The mRNA for HNF-3A is present in the rat liver but not in brain, kidney, intestine, or spleen, and the basis for this difference is cell-specific regulation of HNF-3A gene transcription.

Amino Acid Sequence↗
PubMed2026

Identification of genomic features that uniquely impact estrogen receptor alpha binding and its effects on gene expression in endometrial cancer.

Estrogen receptor 1 (ESR1, also known as estrogen receptor alpha or ER) is an established oncogenic transcription factor in breast and endometrial cancer; however, more is known about the mechanisms controlling ER behavior in breast cancer, and therapies targeting ER have been much more successful in breast cancer. To address this disparity, we characterize the genomic features that control ER in endometrial cancer and determine to what extent these factors differ from those in breast cancer. We focus on the locations of estrogen response elements (EREs), ER's preferred DNA-binding motif, throughout the human genome. To identify factors that predict ER genomic binding and effects on target gene expression, we apply machine learning to genomic data for each ERE in Ishikawa cells (ER-positive endometrial cancer) and T-47D cells (ER-positive breast cancer). Many of these factors, such as chromatin accessibility and histone modifications, are predictive of ER activity in both cell lines. However, the transcription factors that predict ER activity are cell type specific, including FOXA1 and GATA3 in T-47D cells and ETV4 and SOX17 in Ishikawa cells. In addition, the features that predict ER binding and effects on gene expression differ, with transcription at EREs in the absence of estrogen being predictive of ER regulatory activity. A CRISPR knockout screen in Ishikawa cells, as well as follow-up experiments, confirms the discovery that SOX17 controls ER activity in endometrial cancer cells. These results identify important genomic features of ER binding and regulatory activity and how these features differ between endometrial cancer and breast cancer cells.

Humans↗