title: Epigenetic silencing of the chaperone Cosmc in human leukocytes expressing tn antigen.
abstract: Cosmc is the specific molecular chaperone in the endoplasmic reticulum for T-synthase, a Golgi β3-galactosyltransferase that generates the core 1 O-glycan, Galβ1-3GalNAcα-Ser/Thr, in glycoproteins. Dysfunctional Cosmc results in the formation of inactive T-synthase and consequent expression of the Tn antigen (GalNAcα1-Ser/Thr), which is associated with several human diseases. However, the molecular regulation of expression of Cosmc, which is encoded by a single gene on Xq24, is poorly understood. Here we show that epigenetic silencing of Cosmc through hypermethylation of its promoter leads to loss of Cosmc transcripts in Tn4 cells, an immortalized B cell line from a male patient with a Tn-syndrome-like phenotype. These cells lack T-synthase activity and express the Tn antigen. Treatment of cells with 5-aza-2'-deoxycytidine causes restoration of Cosmc transcripts, restores T-synthase activity, and reduces Tn antigen expression. Bisulfite sequencing shows that CG dinucleotides in the Cosmc core promoter are hypermethylated. Interestingly, several other X-linked genes associated with glycosylation are not silenced in Tn4 cells, and we observed no correlation of a particular DNA methyltransferase to aberrant methylation of Cosmc in these cells. Thus, hypermethylation of the Cosmc promoter in Tn4 cells is relatively specific. Epigenetic silencing of Cosmc provides another mechanism underlying the abnormal expression of the Tn antigen, which may be important in understanding aberrant Tn antigen expression in human diseases, including IgA nephropathy and cancer.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Mi
authors.forename: Lina
authors.initials: L
authors.lastname: Song
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Ding
authors.forename: Junwei
authors.initials: J
authors.lastname: Zeng
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lehoux
authors.forename: Rajindra P
authors.initials: RP
authors.lastname: Aryal
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wang
authors.forename: Vanja K
authors.initials: VK
authors.lastname: Crew
authors.forename: Irma
authors.initials: I
authors.lastname: van Die
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cummings
authors.forename: Tongzhong
authors.initials: T
authors.lastname: Ju
mesh_terms: D000595:Amino Acid Sequence; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008745:Methylation; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; C505369:C1GALT1C1 protein, human; D018832:Molecular Chaperones; C040286:Tn antigen; D016695:Glycosyltransferases