Diversity of Alpha-Fetoprotein Gene Expression in Mice Is Generated by a Combination of Separate Enhancer Elements

Hammer, Robert E.; Krumlauf, Robb; Camper, Sally A.; Brinster, Ralph L.; Tilghman, Shirley M.

doi:10.1126/science.2432657

Cited by 308 publications

(208 citation statements)

References 27 publications

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“…First, it has been shown that the AFP gene is expressed in brain and other nonhepatic tissues at particular stages of pre-and postnatal life (1,8,35,38,41). This suggests that nonhepatic AFP gene expression is developmentally regulated, possibly through a mechanism different from that operating in liver tissue (16). ATBF1 may be one of the factors involved in developmental regulation of the AFP gene in nonhepatic tissues.…”

Section: Discussionmentioning

confidence: 99%

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

Yasuda¹,

Mizuno²,

Tamaoki³

et al. 1994

Mol. Cell. Biol.

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ATBF1 is a 306-kDa protein containing four homeodomains, 17 zinc finger motifs, and several segments potentially involved in transcriptional regulation (T. Morinaga, H. Yasuda, T. Hashimoto, K. Higashio, and T. Tamaoki, Mol. Cell. Biol. 11:6041-6049, 1991). At least one of the homeodomains of ATBF1 binds to an AT-rich element in the human a-fetoprotein (AFP) enhancer (enhancer AT motif). In the present work, we analyzed the transcriptional regulatory activity of ATBF1 with respect to the enhancer AT motif and similar AT-rich elements in the human AFP promoter and the human albumin promoter and enhancer. Gel retardation assays showed that ATBF1 binds to the AFP enhancer AT motif efficiently; however, it binds weakly or not at all to other AT-rich elements in the AFP and albumin regulatory regions studied. Alterations of the enhancer AT motif by site-specific mutagenesis resulted in the loss of binding of ATBF1. Cotransfection experiments with an ATBF1 expression plasmid and the chloramphenicol acetyltransferase (CAT) gene fused to AFP promoter or enhancer fragments showed that ATBF1 suppressed the activity of AFP enhancer and promoter regions containing AT-rich elements. This suppression was reduced when the mutated AT motifs with low affinity to ATBF1 were linked to the CAT gene. The ATBF1 suppression of AFP promoter and enhancer activities appeared to be due, at least in part, to competition between ATBF1 and HNF1 for the same binding site. In contrast to the AFP promoter and enhancer, the albumin promoter and enhancer were not affected by ATBF1, although they contain homologous AT-rich elements. These results show that ATBF1 is able to distinguish AFP and albumin AT-rich elements, leading to selective suppression of the AFP promoter and enhancer activities.The regulatory regions of all genes so far studied contain multiple cis-acting elements which interact with trans-acting factors (22,32). Liver-specific gene expression is also achieved through a combinatorial action of regulatory DNA elements and interacting transcription factors (20,21,30). One characteristic feature of a number of liver-specific promoters is the presence of DNA sequences having a well-organized array of 10 to 11 adenine (A) and thymine (T) residues sandwiched by a guanine (G) and a cytosine (C) (AT-rich element) (4-7, 11, 15, 23, 26, 40). These elements have been shown to be the binding sites of a liver-enriched transcription factor, HNF1 (also called LF-B1 and APF) (3-6, 12, 31). Mutations of the AT-rich element cause drastic reduction of liver-specific transcriptional activity both in vitro and in vivo (21, 28, 33, 42), indicating that the AT-rich element and HNF1 play a crucial role in liver-specific promoter activation.In the promoters of a-fetoprotein (AFP) genes of mice, rats, and humans, two HNF1-binding sites are conserved. In the enhancers, on the other hand, the AT-rich element is present in the human AFP gene but not in the mouse and rat genes (13). The human AFP enhancer AT motif is also unique in that HNF1 binds to it 10-fold...

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Section: Discussionmentioning

confidence: 99%

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

Yasuda¹,

Mizuno²,

Tamaoki³

et al. 1994

Mol. Cell. Biol.

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“…The expression of the fusion gene, however, was affected by its chromosomal position as observed in a number of other transgenes (Kollias et al, 1986;Hammer et al, 1987). As a result, brain localization of the expression varied among transgenic mice as seen Fig.…”

Section: Diversity Of Gene Expression In the Cnsmentioning

confidence: 92%

Position‐independent, high‐level, and correct regional expression of the rat aldolase C gene in the central nervous system of transgenic mice

Kajihara

Masuda

Oh‐ishi

et al. 1994

European Journal of Biochemistry

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Aldolase C is mainly expressed in the central nervous system (CNS). To clarify the regulatory mechanisms for the CNS-specific expression, transgenic mice were created using two constructs of the rat aldolase C gene. A fusion gene comprising the 5' regulatory region of the aldolase C gene was expressed in a CNS-specific manner. However, the expression levels and the cellular localization of the gene varied among transgenic mice. The other construct, including both 5' and 3' regulatory regions of the gene, showed position-independent and high-level expression as well as the correct regional distribution in the CNS. These results indicate that the 13-kb sequence of the rat aldolase C gene contains sufficient information for faithful expression of the gene.Tissue-specific expression of genomic information mainly occurs through transcriptional regulation. In eukaryotes, however, DNA is complexed with histone to form compact chromatin structures and the regulatory mechanism of gene expression is complex. The structures of chromosomes are important not only in the compaction of the chromatin fiber, but also in the utilization of genomic information (Mirkovitch et al., 1984). Therefore, it is a requisite for understanding the regulatory mechanisms of gene expression to elucidate how to open chromatin structure. To solve this problem, a number of genes have been used to create transgenic mice. In transgenic animals, however, those genes were frequently affected by the site of the integration (Palmiter and Brinster,

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“…Studies with cultured cells also revealed, once again like oel, that enhancer components can have positive or negative effects on the inducibility or the celltype specificity of the enhancer influences (e.g., Wasylyk and Wasylyk 1986;Hammer et al 1987;Imler et al 1987;Kuhlemeier et al 1987; Goodbourn and Maniatis…”

Section: Component Structure Of Oelmentioning

confidence: 96%

Ovarian follicle cell enhancers from the Drosophila yolk protein genes: different segments of one enhancer have different cell-type specificities that interact to give normal expression.

Logan

Wensink²

1990

Genes Dev.

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This paper examines ovarian transcription of the divergently oriented yolk protein genes 1 and 2 (ypl and yp2) of Drosophila melanogaster. We report germ line transformation results demonstrating that ypl and yp2 are transcribed in the same subpopulations of ovarian follicle cells. Our results show that this expression pattern is directed by two enhancers: ovarian enhancer 1, located between the genes, and ovarian enhancer 2, located within the first exon of yp2. Analysis of the expression pattern resulting from alterations in ovarian enhancer 1 demonstrates that different segments of this enhancer have different positive or negative effects on the cell-type specificity of transcription.

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Diversity of Alpha-Fetoprotein Gene Expression in Mice Is Generated by a Combination of Separate Enhancer Elements

Cited by 308 publications

References 27 publications

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

Position‐independent, high‐level, and correct regional expression of the rat aldolase C gene in the central nervous system of transgenic mice

Ovarian follicle cell enhancers from the Drosophila yolk protein genes: different segments of one enhancer have different cell-type specificities that interact to give normal expression.

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