title: Promoters of Human Cosmc and T-synthase Genes Are Similar in Structure, Yet Different in Epigenetic Regulation.
abstract: 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 Krüppel-like transcription factors, including SP1/SP3, respectively. Methylome analysis of Tn4 B cells, which harbor a silenced Cosmc, confirmed the hypermethylation of the Cosmc core promoter but not for T-synthase. These results demonstrate that Cosmc and T-synthase are transcriptionally regulated at a basal level by the specificity protein/Krüppel-like transcription factor family of members, which explains their ubiquitous and coordinated expression, and also indicate 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.
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Junwei
authors.initials: J
authors.lastname: Zeng
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Mi
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Human Genetics, and.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Genetics, and.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Human Genetics, and.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Lina
authors.initials: L
authors.lastname: Song
authors.affiliation: the Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: van Die
authors.affiliation: Medicine, Emory University School of Medicine, Atlanta, Georgia 30322 and.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.affiliation: Human Genetics, and.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: From the Departments of Biochemistry, tju@emory.edu.
authors.forename: Tongzhong
authors.initials: T
authors.lastname: Ju
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020862:GC Rich Sequence; D005700:Galactosyltransferases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism
chemical_list: C505369:C1GALT1C1 protein, human; D018832:Molecular Chaperones; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D051705:Sp3 Transcription Factor; C505293:C1GALT1 protein, human; D005700:Galactosyltransferases
keywords: Cosmc; DNA methylation; IgA nephropathy; T-synthase; gene regulation; glycosylation; promoter; transcription