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

Bo Yan, Joris Heus, Nina Lu, Ralph C. Nichols, Nina Raben, Paul H. Plotz

Research output: Contribution to journalArticlepeer-review

Abstract

Acid α-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 α-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 α-glucosidase gene as well as other lysosomal enzyme genes.

Original languageEnglish (US)
Pages (from-to)1789-1793
Number of pages5
JournalJournal of Biological Chemistry
Volume276
Issue number3
StatePublished - Jan 19 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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