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 ge...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-01, Vol.276 (3), p.1789-1793
Main Authors: Yan, B, Heus, J, Lu, N, Nichols, R C, Raben, N, Plotz, P H
Format: Article
Language:English
Subjects:
alpha-Glucosidases - genetics
Base Sequence
Basic Helix-Loop-Helix Transcription Factors
DNA Primers
DNA-Binding Proteins - metabolism
Erythroid-Specific DNA-Binding Factors
Gene Expression Regulation, Enzymologic
Hes-1 protein
Homeodomain Proteins - metabolism
Humans
Introns
Plasmids
Repressor Proteins - genetics
Sequence Deletion
TK gene
Transcription Factor HES-1
Transcription Factors - metabolism
Transcription, Genetic
Transfection
YY1 protein
YY1 Transcription Factor
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Summary: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.
ISSN:0021-9258
DOI:10.1074/jbc.M005959200