DNA methylation status of the MUC1 gene coding for a breast-cancer-associated protein.
The MUC1 gene codes for protein products that are highly expressed in human breast-cancer tissue and that serve as tumor markers for disease progression. The factors contributing to the disease-specific over-expression of the MUC1 gene are under intensive investigation and are yet to be determined. A large transcribed region of the human MUC1 gene is a CpG island that consists of 60-bp tandemly repeating units, each of which contains one SmaI restriction site. The methylation status of regulatory regions, upstream to the transcriptional start site, is essential for the regulation of gene expression. We therefore evaluated whether the methylation status of the various regions of the MUC1 gene may affect its expression. Using SmaI, and its isoschizomer XmaI endonucleases, we demonstrated that in peripheral-blood leukocytes (PBL-DNA) that do not express the MUC1 gene, the repeat array is completely methylated, whereas the same sequences are entirely non-methylated in breast-tumor-tissue DNA (BT-DNA). In contrast, sequences upstream and downstream to the repeat array showed no difference in the methylation pattern in PBL-DNA and BT-DNA. Hypomethylation within the repeat array was also observed in other epithelial tissues that express the MUC1 gene at much lower levels to those seen in breast-cancer tissue. These studies demonstrate that hypomethylation of the tandem repeat array is an absolute requirement for MUC1 gene expression in epithelial tissues, although in breast-cancer tissue additional regulatory mechanisms must pertain for its over-expression.
Zrihan-Licht
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S
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv, Israel.
Weiss
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M
Keydar
I
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Wreschner
D H
DH
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008745:Methylation; D008969:Molecular Sequence Data; D018396:Mucin-1; D009077:Mucins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic
D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D018396:Mucin-1; D009077:Mucins; D009363:Neoplasm Proteins