title: Transcriptional regulation of the human acid alpha-glucosidase gene. Identification of a repressor element and its transcription factors Hes-1 and YY1.
abstract: Acid alpha-glucosidase, the product of a housekeeping gene, is a lysosomal enzyme that degrades glycogen. A deficiency of this enzyme is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenesis type II. We have previously demonstrated that the human acid alpha-glucosidase gene expression is regulated by a silencer within intron 1, which is located in the 5'-untranslated region. In this study, we have used deletion analysis, electrophoretic mobility shift assay, and footprint analysis to further localize the silencer to a 25-base pair element. The repressive effect on the TK promoter was about 50% in both orientations in expression plasmid, and two transcriptional factors were identified with antibodies binding specifically to the element. Mutagenesis and functional analyses of the element demonstrated that the mammalian homologue 1 of Drosophila hairy and Enhancer of split (Hes-1) binding to an E box (CACGCG) and global transcription factor-YY1 binding to its core site function as a transcriptional repressor. Furthermore, the overexpression of Hes-1 significantly enhanced the repressive effect of the silencer element. The data should be helpful in understanding the expression and regulation of the human acid alpha-glucosidase gene as well as other lysosomal enzyme genes.
authors.affiliation: Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.
authors.forename: B
authors.initials: B
authors.lastname: Yan
authors.forename: J
authors.initials: J
authors.lastname: Heus
authors.forename: N
authors.initials: N
authors.lastname: Lu
authors.forename: R C
authors.initials: RC
authors.lastname: Nichols
authors.forename: N
authors.initials: N
authors.lastname: Raben
authors.forename: P H
authors.initials: PH
authors.lastname: Plotz
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D015971:Gene Expression Regulation, Enzymologic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007438:Introns; D010957:Plasmids; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D050986:YY1 Transcription Factor; D000520:alpha-Glucosidases / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D050986:YY1 Transcription Factor; D000520:alpha-Glucosidases; C494698:YY1 protein, human; C078493:HES1 protein, human