A genetic analysis of extinction: trans-regulation of 16 liver-specific genes in hepatoma-fibroblast hybrid cells.

Chin, Alice; Fournier, R. E. K.

doi:10.1073/pnas.84.6.1614

Cited by 57 publications

(27 citation statements)

References 33 publications

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“…Expression of the TAT gene, as well as of several other liver-specific genes, is reduced >500-fold in these hepatoma/fibroblast hybrid crosses in comparison with FTO-2B cells (data not shown) in agreement with a previous report (Chin and Foumier 1987). As a first step in understanding the mechanisms leading to this complete repression, we compared the chromatin structure of the TAT gene, reflected in DNase I hypersensitive sites (HSs), in extinguished hybrids and the parental hepatoma and fibroblast cells.…”

Section: Extinction Of Tat Gene Activity In Hepatoma/ Fibroblast Hybrsupporting

confidence: 80%

“…Whereas in monochromosomal hybrids, containing an active fibroblast-derived TSE1 locus, only a subset of liver genes are extinguished, in whole-cell hybrids all liver-specific functions are affected (Chin and Foumier 1987;Lem et al 1988;Ruppert et al 1990). Moreover, comparison of TAT gene activity in these two hybrid systems has indicated striking quantitative and qualitative differences.…”

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confidence: 99%

“…Second, in hepatoma microcell hybrids, which contain only one or few fibroblast chromosomes, the extinction of subsets of liver genes can be correlated with the retention of specific nonhepatic chromosomes, an observation that has led to the definition of so-called tissue-specific extinguisher (TSE) loci (Killary and Fournier 1984;Petit et al 1986;Chin and Foumier 1989). The reversibility of the active and inactive state of a particular gene attests to the above-mentioned notion that both activation and extinction are processes that are actively maintained.…”

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confidence: 99%

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Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcriptional activators.

Nitsch¹,

Boshart²,

Schütz³

1993

Genes Dev.

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Extinction is defined as the loss of cell type-specific gene expression that occurs in somatic cell hybrids derived by fusion of cells with dissimilar phenotypes. To explore the basis of this dominant-negative regulation, we have studied the activities of the control elements of the liver-specific gene encoding tyrosine aminotransferase (TAT) in hepatoma/fibroblast hybrid crosses. We show that extinction in complete somatic cell hybrids is accompanied by the loss of activity of all known cell type-specific control elements of the TAT gene. This inactivity is the result of first, lack of expression of genes coding for the transcriptional activators HNF4 and HNF3[~ and HNF33,, which bind to essential elements of the enhancers; and second, loss of in vivo binding and activity of ubiquitous factors to these enhancers, including CREB, which is the target for repression by the tissue-specific extinguisher locus TSE1. Complete extinction of TAT gene activity is therefore a multifactorial process affecting all three enhancers controlling liver-specific and hormone-inducible expression. It results from lack of activation, rather than active repression, and involves both post-translational modification and loss of essential transcriptional activators.[Key Words: Extinction; tyrosine aminotransferase; chromatin; HNF3; HNF4; somatic cell hybrids] Received September 14, 1992; revised version accepted November 23, 1992.A particular cellular phenotype, characterized by the expression of distinct sets of genes, is thought to be determined by the action of positively and negatively acting regulatory proteins. This combinatorial control of gene activity involves the binding of multiple trans-acting factors to distinct cis regulatory elements. The differentiated state usually has to be actively maintained and continually transmitted (for review, see Blau 1992). Striking examples for this requirement of continual regulation are presented by the autoregulatory loops discovered in the maintenance of the muscle phenotype involving MyoD as a positive regulator (for review, see Weintraub et al. 1991) and by proteins of the polycomb group, among which are negative regulators required for differential expression of homeotic genes along the anteriorposterior axis of the Drosophila embryo (for review, see Paro 1990).Whereas many cell type-specific positive regulators have been characterized, the role of negatively acting regulatory proteins in specifying a particular cellular phenotype is less clear, although several examples of repressor-like activities have been described (for review,

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Section: Extinction Of Tat Gene Activity In Hepatoma/ Fibroblast Hybrsupporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcriptional activators.

Nitsch¹,

Boshart²,

Schütz³

1993

Genes Dev.

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“…All of the genes repressed by TSEl are normally inducible via the CAMP signal transduction pathway (Ruppert et al, 1990). Other extinguisher loci regulate expression of distinct sets of genes in hepatic cells, as all liver-specific traits are extinguished in karyotypically complete hepatoma x fibroblast hybrids (Chin and Fournier, 1987). For example, Tse-2 on mouse chromosome 1 represses expression of the serum albumin and alcohol dehydrogenase genes (Petit et al, 1986;Chin and Fournier, 1989).…”

Section: Introductionmentioning

confidence: 99%

The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-Dependent protein kinase

Boshart

Weih

Nichols

et al. 1991

Cell

180

100

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“…Studies on somatic cell hybrids have shown that (i) the fusion of a cell line that expresses a specific gene product with a nonexpressing cell line leads to extinction of the tissue-specific product in the stable hybrid (8,13,16,23,34) and (ii) the fusion of a normal with transformed cell frequently yields untransformed hybrids (12,19,31). In both cases, the hybrid phenotypes (extinction and suppression of transformation) appear to be linked to specific genetic loci (termed extinguishers for the intertypic hybrids) (23).…”

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confidence: 99%

Extinction and activation of the thyroglobulin promoter in hybrids of differentiated and transformed thyroid cells.

Bonapace¹,

Sanchez²,

Obici³

et al. 1990

Mol. Cell. Biol.

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Thyroglobulin gene expression was repressed in a rat thyroid cell line transformed with Kirsten murine sarcoma virus. Expression of a dominant selectable marker driven by the thyroglobulin promoter was also inhibited. Somatic cell hybridization of transformed and differentiated thyroid cells resulted in extinction of thyroglobulin gene expression. When transformed cells carrying a dominant selectable marker driven by the thyroglobulin promoter were fused to differentiated cells and expression of this marker was selected, we obtained stable hybrid cell lines expressing both the endogenous and the exogenous thyroglobulin promoters. Although the expression of v-ras remained unchanged compared with expression in the parental transformed cells, transformation was suppressed in the hybrid cell lines. The other thyroid differentiation markers, iodide uptake and thyroid-stimulating hormone-dependent growth, were inhibited in all the hybrids tested. We show that activity of the thyroglobulin promoter correlates with the presence of a thyroid nuclear factor that binds the promoter at position -60 from the transcription start site. Loss of this factor accompanies the extinction of thyroglobulin gene expression in hybrids selected for expression of a non-thyroid-specific promoter.

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A genetic analysis of extinction: trans-regulation of 16 liver-specific genes in hepatoma-fibroblast hybrid cells.

Cited by 57 publications

References 33 publications

Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcriptional activators.

Extinction of tyrosine aminotransferase gene activity in somatic cell hybrids involves modification and loss of several essential transcriptional activators.

The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-Dependent protein kinase

Extinction and activation of the thyroglobulin promoter in hybrids of differentiated and transformed thyroid cells.

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