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J. Biol. Chem., Vol. 276, Issue 3, 1789-1793, January 19, 2001

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Transcriptional Regulation of the Human Acid -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, and Paul H. Plotz

From the  Arthritis and Rheumatism Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892-1820, ^§ Pharming Technologies B.V., Niels Bohrweg 11-13, 2333 CA Leiden, The Netherlands, and ^¶ Dartmouth Medical School, Lebanon, New Hampshire 03756

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

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