Regulation of the hypoxanthine phosphoribosyltransferase gene: in vitro and in vivo approaches.
The hypoxanthine phosphoribosyltransferase (HPRT) locus is a constitutively expressed housekeeping gene characterized by a notably higher level of expression in the mammalian brain. The enzyme it encodes is key to purine salvage in humans and is the basis for the X-linked recessive disorder, Lesch-Nyhan syndrome (LNS). Methylation in the promoter plays a critical, if not fully understood, role in transcriptional silencing of the locus on the inactive chromosome, possibly by conferring structural stability. In vivo footprinting assays of the promoter region have shown protein interaction with multiple Spl-binding sites, a possible AP2 site, and a potentially novel binding site. In vitro studies of HPRT promoter deletion constructs have identified a minimal promoter element necessary for maximal transcription and a position-dependent, orientation-independent repressor element (HPRT-NE) that functions on heterologous promoters. Regulatory intron elements have also been observed. Studies on transgenic mice bearing HPRT promoter constructs have shown that the minimal promoter element is insufficient for in vivo expression and that HPRT-NE is responsible for conferring neuronal specificity. HPRT-mice possess metabolic defects similar to LNS patients, but fail to develop human behavioral abnormalities, perhaps because of species differences in purine metabolism. A neuronal-specific protein complex appears to be necessary for activator function of HPRT-NE, while a ubiquitously expressed complex may be responsible for repression. Sequence analysis Indicates that the latter complex may depend on the multifunctional transcription factor YY1 for binding. A fuller understanding of HPRT gene regulation will hopefully provide insight into the transcriptional mechanisms controlling the expression of housekeeping and brain-specific genes.
Jiralerspong
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Department of Neurology, Baylor College of Medicine, Houston, Texas 77030-3411, USA.
Patel
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PI
D000818:Animals; D015210:Arthritis, Gouty / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004790:Enzyme Induction; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D007926:Lesch-Nyhan Syndrome / Q000201:enzymology / Q000235:genetics; D008297:Male; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D011401:Promoter Regions, Genetic; D011544:Pseudogenes; D011687:Purines / Q000378:metabolism; D012377:Rodentia / Q000235:genetics; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics; D050986:YY1 Transcription Factor
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D009419:Nerve Tissue Proteins; D011687:Purines; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C494699:Yy1 protein, mouse; D007041:Hypoxanthine Phosphoribosyltransferase