Promoters of Human Cosmc and T-synthase Genes Are Similar in Structure, Yet Different in Epigenetic Regulation.

The T-synthase (Core 1 β3-galactosyltransferase) and its molecular chaperone Cosmc regulate the biosynthesis of mucin type O-glycans on glycoproteins, and evidence suggests that both T-synthase and Cosmc are transcriptionally suppressed in several human diseases, although the transcriptional regulation of these two genes is not understood. Here we characterized the promoters essential for human Cosmc and T-synthase transcription. The upstream regions of the genes lack a conventional TATA box but contain CpG-islands: cCpG-I and cCpG-II for Cosmc and tCpG for T-synthase. Using luciferase reporter assays, site-directed mutagenesis, ChIP assays, and Mithramycin A treatment, we identified the core promoters within cCpG-II and tCpG, which contain two binding sites for Kruppel-like transcription factors (KLF), including SP1/SP3, respectively. Methylome analysis of Tn4 B cells, which harbor a silenced Cosmc, confirmed the hypermethylation of Cosmc core promoter, but not for that of T-synthase. These results demonstrate that Cosmc and T-synthase are transcriptionally regulated at a basal level by SP/KLF family transcription factors, which explains their ubiquitous and coordinated expression, and also indicates that they are differentially epigenetically regulated beyond X-chromosome imprinting. These results are important in understanding the regulation of these genes that have roles in human diseases, such as IgA Nephropathy and cancer. [ABSTRACT FROM AUTHOR]