Coordinate regulation of two genes encoding gluconeogenic enzymes by the trans-dominant locus Tse-1.

Abstract

Tissue-specific extinguisher-i (Tse-1) is a mouse genetic locus that can repress liver-specific tyrosine aminotransferase gene expression in trans. To search for other Tse-l-responsive genes, hepatoma microcell hybrids retaining mouse chromosome 11 or human chromosome 17, containing murine Tse-1 and human TSEI, respectively, were screened for expression of liver-specific mRNAs. While most liver gene activity was unaffected in such hybrids, phosphoenolpyruvate carboxykinase and tyrosine aminotransferase gene expression was coordinately repressed in these clones. Extinction of both genes was apparently mediated by a single genetic locus that resides on human chromosome 17.Cellular differentiation is generally viewed as an orchestrated process in which specific gene sets are activated or repressed at defined developmental times. These events culminate in the establishment of lineage-dependent patterns of transcription that are the basis of cell specialization. The molecular mechanisms that control these processes are poorly understood.Tissue-specific genes are primarily regulated at the level of transcription (1, 2), and discrete sequence elements are required in cis for proper developmental control (3). These observations support the widely-held view that trans-acting factors play key roles in regulating eukaryotic gene activity. Further analysis of this mechanism of gene control will require the characterization of specific regulatory factors in both genetic and biochemical terms.The first clear evidence for trans-regulation of differentiated functions in mammalian cells was reported by Davidson et al. in 1966 (4). They observed that melanoma-fibroblast hybrid cells failed to produce the melanin pigment characteristic of their differentiated melanoma parent. This "extinction" phenomenon proved to be both general and bidirectional: most stable hybrids formed by fusing distinctly different cell types fail to express the tissue-specific products of either parent (5, 6). However, extinguished traits can be reexpressed in hybrid segregants that have eliminated chromosomes of one of the parental cells (7-9). In reexpressing segregants, heterologous gene activation may be observed (10, 11). Thus, expression of tissue-specific genes can be manipulated experimentally in intertypic hybrids, and this provides a system with the potential to define genetic factors that regulate gene activity in trans.Liver-specific gene expression in intertypic hepatoma hybrids has been studied for many years, and, thanks largely to the work of Weiss and coworkers (7-11), this remains the most comprehensively analyzed hybrid cell system to date. Two important facts about tissue-specific gene expression in this system have recently been established. First, virtually all liver-specific gene activity is repressed in genotypically complete rat hepatoma-mouse fibroblast hybrids, but reexpression occurs upon loss of relatively few fibroblast chromosomes (12). Second, extinction of particular liver genes is mediated by discrete genetic loci...

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

“…This led to the definition of tissue-specific extinguisher loci (reviewed in [166]). The Tse-J locus is responsible for the extinction of the PEPCK, tyrosine aminotransferase and aldolase B genes in hybrid cells [167]. The product of the Tse-J locus is the regulatory subunit RIa of PKA [168,169].…”

Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes

“…Clone 7AE-27 retains several human chromosome 17 markers including human 7&e-l. 7AD-7 retains a subset of these markers but is Tse-l- (Lem et al, 1988). Interestingly, several a/f-responsive genes are responsive to the presence of Tse-7 (Figure 6, compare lanes 1 and 5).…”

“…Extinction has been shown to have a specific genetic basis (Killary and Fournier, 1984). For example, it has been shown that the presence of a segment of human chromosome 17 is sufficient to extinguish TAT and PEPCK expression in rat hepatoma cells, suggesting that a single genetic locus, denoted Be-7 (tissue-specific extinguisher l), is responsible for extinction of these genes (Lem et al, 1988). Since TAT and PEPCK both require a/f for liverspecific expression, we hypothesized that other genes affected by a/f might also be regulated by Tse-1.…”

“…In hepatoma hybrids retaining mouse chromosome 11 or a specific region of human chromosome 17, TAT and PEPCK gene expression is selectively repressed, while expression of other liver genes is unaffected (Lem et al, 1988). This trans-dominant effect is mediated by a genetic locus designated tissue-specific extinguisher 1 (Tse-7) (Killary and Fournier, 1984).…”

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

“…Analyses of microcell hybrids containing parts of the long arm of fibroblast-derived human chromosome 17 in a hepatoma cell background have defined an extinguisher locus that influences many or possibly all cAMPregulated liver functions, including expression of the tyrosine aminotransferase (TAT) and phosphoenol pyrurate carboxykinase (PEPCK) genes (TSE1; Killary and Fournier 1984;Lem et al 1988;Thayer and Fournier 1989;Ruppert et al 1990). Recently, we identified a cAMP response element (CRE) in a liver-specific enhancer of the TAT gene as the target of TSEl-dependent extinction ) and, subsequently, showed TSE1 to be the regulatory subunit Rim of protein kinase A (Boshart et al 1991a;Jones et al 1991).…”