Transcriptional regulation of the human acid alpha-glucosidase gene - Identification of a repressor element and its transcription factors Hes-1 and YY1

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 locate d in the 5'-untranslated region. In this study, we have used deletion analy sis, electrophoretic mobility shift assay, and footprint analysis to furthe r 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 spe cifically to the element. Mutagenesis and functional analyses of the elemen t demonstrated that the mammalian homologue 1 of Drosophila hairy and Enhan cer of split (Hes-l) 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-l significantly enhanced the repre ssive effect of the silencer element. The data should be helpful in underst anding the expression and regulation of the human acid alpha -glucosidase g ene as well as other lysosomal enzyme genes.