Transcription factors and liver-specific genes (original) (raw)
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Two distinct factors interact with the promoter regions of several liver-specific genes
The EMBO journal, 1988
A segment of the human alpha 1-antitrypsin (alpha 1AT) 5'-flanking region comprising nucleotides -137 to -37 from the start of transcription is sufficient to drive liver-specific transcription from the homologous alpha 1AT promoter and from the heterologous SV40 promoter. In this paper we characterize two proteins, LF-A1 and LF-B1, whose ability to bind wild-type and mutant alpha 1AT promoter segments correlates with the ability of these segments to activate transcription in vivo. DNase I protection and methylation interference analysis reveals that LF-A1 recognizes sequences present in the regulatory region of the human alpha 1-antitrypsin, apolipoprotein A1 and haptoglobin-related genes. These sequences share a common 5' TGG/A A/C CC 3' motif. LF-B1 binds to the palindrome 5' TGGTTAAT/ATTCACCA 3' which is present in the human alpha 1-antitrypsin gene between positions -78 and -62 from the start of transcription. LF-B1 also recognizes a related sequence present ...
Mechanisms of liver-specific gene expression
Current Biology, 1992
Significant advances in the field of hepatocyte-specific gene expression have been made during the past year. Several new transcription factors have been cloned and partially characterized. Analyses of the promoter regions of several factors have also been initiated and Drosophila homologs for two of these factors have been found, opening the way for studies on development.
Nucleic Acids Research, 1989
The proximal promoter region of the human transferrin gene contains an hepatocyte-specific cis-element (PRI, nucleotides -76 to -51) whose DNA sequence is homologous to a sequence (nucleotides -89 to -68) present in the transcriptionally essential 5' region of the human antithrombin III gene and to another hepatocyte-specific sequence (A domain) of the human a 1 -antitrypsin gene promoter. The results reported here lead to the conclusion that the liver trans-acting factor Tf-LF1, binding to the transferrin PRI cis-element interacts with the homologous antithrombin III region, but is different from the transcription factor LF-A1 interacting with the A domain of the a l-antitrypsin promoter.
Proceedings of the National Academy of Sciences, 1991
The transcription factors that act in hepatocyte-specific gene expression include proteins that are present mainly in liver cells (HNF-1/LFB1, C/EBP, HNF-3, HNF-4) (HNF, hepatocyte nuclear factor; C/EBP, rat enhancer binding protein) and proteins that are widely distributed (AP-1, NF-1, NF-Y/ACF). We show here that the genes encoding each of these liver-enriched factors exhibit different patterns of transcriptional control in different tissues. In addition, there were several instances in which transcription was detected (e.g., for HNF-1) when no mRNA or specific DNA binding protein was found, suggesting the importance of posttranscriptional control in some instances for these factors. These experiments identify C/EBP, HNF-3, and HNF-4, and perhaps also HNF-1, as targets for the study of cascades of transcriptionally controlled transcription factors in differentiated cells.
A NovelHepatocytic Transcription Factor ThatBindsthe aFetoprotein Promoter-Linked Coupling Element
1994
P Wen and J Locker coupling element. binds the alpha-fetoprotein promoter-linked A novel hepatocytic transcription factor that http://mcb.asm.org/content/14/10/6616 Updated information and services can be found at: These include: CONTENT ALERTS more» cite this article), Receive: RSS Feeds, eTOCs, free email alerts (when new articles http://journals.asm.org/site/misc/reprints.xhtml Information about commercial reprint orders: http://journals.asm.org/site/subscriptions/ To subscribe to to another ASM Journal go to: on March 2, 2013 by guest
Gene regulation in rodent hepatocytes during development, differentiation and disease
European Journal of Biochemistry, 1993
The expression of genes in the liver is mostly controlled at the transcriptional level and depends on the regulatory interactions between cis-acting sequences and trans-acting molecules. Proximal promoters and distant enhancers in combination with a number of hepatocyte-enriched DNA-binding proteins and general transcription factors interact specifically with these elements and control the expression of liver-specific genes. Hepatocyte-enriched regulatory proteins have been isolated from liver nuclear extracts, characterized, and their corresponding genes have been cloned. These include the hepatocyte nuclear factors 1, 3, 4 (HNF-1,3,4), some members of the CAAATIenhancer binding protein (CEBP) family, and D site binding protein (DBP). These factors belong to larger families and are able to form heterodimers, perhaps with the exception of the HNF-3 family, with other members of the same family. Interestingly, the majority of the genes encoding such proteins are themselves regulated at the transcriptional level, although both transcriptional and post-transcriptional events modulate their expression during development, hepatocyte differentiation and disease, suggesting that a transcriptional cascade may play a critical role in mammalian liver development and differentiation. Cellular proliferation and differentiation during development is controlled by many regulatory processes. These include the selective induction, expression and regulation of the activity of genes which are likely to encode for DNAbinding proteins or proteins that interact with them and control the transcription of several other genes. Thus a cascade of transcriptional activities is initiated that will direct development and differentiation to the adult phenotype [l -31. The study of liver development and differentiation offers many opportunities to address these questions at the molecular level. Rodent liver organogenesis has been thoroughly studied at the cellular level. It is now known that at day eight of embryonal development the endodermal cells of the developing foregut are induced by the precardiac mesenchyme and approximately one day later the hepatic endoderm will emerge from the gut endoderm. Subsequently the primary liver diverticulum invades the mesenchyme of the septum transversum. During this stage, proliferation and differentiation of the hepatic endoderm into hepatoblasts occurs.
Nucleic Acids Research, 2002
In animals, transcription factor binding sites are hard to recognize because of their extensive variation. We therefore characterized the general relationship between a speci®c protein-binding site and its DNA sequence and used this relationship to generate a predictive algorithm for searching other DNA sequences. The experimental process was de®ned by studying hepatocyte nuclear factor 1 (HNF1), which binds DNA as a dimer on two inverted-repeat 7-bp half sites separated by one base. The binding model was based on the equivalence of the two half sites, which was con®rmed in examples where speci®c modi®ed sites were compared. Binding competition analysis was used to determine the effects of substitution of all four bases at each position in the half site. From these data, a weighted half-site matrix was generated and the full site was evaluated as the sum of two halfsite scores. This process accurately predicted even weak binding sites that were signi®cantly different from the consensus sequence. The predictions also showed a direct correlation with measured protein binding.
Molecular and cellular biology, 1989
Transthyretin (TTR) and alpha 1-antitrypsin (alpha 1-AT) are expressed at high levels in the liver and also in at least one other cell type. We report here a detailed analysis of the proximal regulatory region of the TTR gene, which has uncovered two new DNA-binding factors that are present mainly (or only) in hepatocytes. One of these new factors, hepatocyte nuclear factor 3 (HNF-3), binds to two sites that are crucial in TTR expression as well as to two additional sites in the alpha 1-AT proximal enhancer region. The second new factor, HNF-4, binds to two sites in TTR that are required for gene activity. We had previously identified binding sites for another hepatocyte-enriched DNA-binding protein (C/EBP or a relative thereof), and additional promoter-proximal sites for that protein in both TTR and alpha 1-AT are also reported here. From these results it seems clear that cell-specific expression is not simply the result of a single cell-specific factor for each gene but the result...
Liver-specific Enhancer of the Glucokinase Gene
Journal of Biological Chemistry, 1996
Glucokinase gene regions that are important for liver specific expression of the enzyme have been functionally identified using transient transfection of rat hepatocytes. Maximal luciferase activity was elicited by a reporter plasmid with 3.4 kilobase pairs of genomic DNA flanking the liver glucokinase promoter. Deletion of a gene fragment between ؊1000 and ؊600 with respect to the start of transcription resulted in a 60% decrease in luciferase activity. Further reduction, close to background level, occurred upon deletion of a 90-base pair sequence between ؊123 and ؊34. Reporter plasmids with the liver glucokinase promoter and any length of flanking sequence were minimally active in INS-1 insulinoma cells, and conversely reporters with the -cellspecific promoter were ineffective in primary hepatocytes. In FTO-2B hepatoma cells, a differentiated line expressing many liver-specific traits but not the endogenous glucokinase gene, the promoter proximal region between ؊123 and ؊34 markedly stimulated the expression of transfected plasmids above background. However, addition of the flanking region up to ؊1000 inhibited luciferase expression. The gene fragment from ؊1003 to ؊707 was shown to be a bona fide, hepatocytespecific enhancer by the following criteria: 1) it stimulated reporter expression by more than 10-and 5-fold when inserted directly upstream of the glucokinase TATA box or complete promoter, respectively, regardless of orientation; 2) it stimulated gene expression from the heterologous SV 40 promoter 4-fold; 3) it was also effective from a downstream position; and 4) in contrast to the enhancer effect in primary hepatocytes, the sequence acted as a silencer in FTO-2B cells and was neutral in INS-1 cells. Both the promoter proximal and the enhancer regions were marked by DNase I hypersensitive sites in the chromatin of primary hepatocytes but not hepatoma or insulinoma cells. Seven footprinted elements termed A through G were mapped in the enhancer by the in vitro DNase I protection assay. Elements A-C may bind liver enriched factors, because they were not protected by spleen nuclear extract. In hepatocyte transfection, the downstream half of the enhancer containing elements A-C was about half as effective as the complete enhancer in stimulating glucokinase promoter activity. Site-directed mutagenesis of element A virtually abrogated the activity of the half-enhancer, whereas mutation of element C had a more moderate effect. The sequence between ؊732 and ؊578 upstream of the liver start of transcription in the human glucokinase gene displays 79% sequence identity with the downstream half of the rat enhancer. The human gene fragment ligated to the minimal rat liver glucokinase promoter was shown to work as an enhancer in the hepatocyte transfection system.