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Background & Aims: Glutamate decarboxylase 1 (GAD1) is up-regulated in neoplastic tissues, but the mechanisms underlying this up-regulation remain unclear.In contrast to the concept that DNA methylati
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Background & Aims: Glutamate decarboxylase 1 (GAD1) is up-regulated in neoplastic tissues, but the mechanisms underlying this up-regulation remain unclear.In contrast to the concept that DNA methylation silences gene transcription, we demonstrate that the human GAD1 promoter is hypermethylated both in cancer cells and in clinical samples that express high levels of GAD1.Methods & Results: The key locus responsible for GAD1 activation has been mapped to a DNA methylation-sensitive CTCF binding site (CTCF-BS3) and a site containing Fuzzy Tandem Repeats (FTRs) for ZNF263 binding.Based on the results of Chromatin Conformation Capture and histone modification marker analysis, we propose that, in normal cells, CTCF binding to CTCF-BS3 could act as a bridge to recruit the ZNF263/SETDB1 repressosome to the GAD1 promoter, which is an effect that might be inhibited by DNA methylation in cancer cells.Conclusions: Consequently, the repressosome might be excluded from the promoter, resulting in GAD1 reactivation.To our knowledge, this is the first time that a mechanism underlying DNA methylation-mediated gene activation in cancer has been revealed.In addition, these results also provide new insights into the function of CTCF in local gene regulation by chromatin loop formation between an intragenic region and the 5-UTR.
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