title: Regulation of chondroitin-4-sulfotransferase (CHST11) expression by opposing effects of arylsulfatase B on BMP4 and Wnt9A.
abstract: In this report, the gene regulatory mechanism by which decline in arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) reduces CHST11 (chondroitin-4-sulfotransferase; C4ST) mRNA expression in human colonic epithelial cells and in colonic epithelium of ARSB-deficient mice is presented. ARSB controls the degradation of chondroitin 4-sulfate (C4S) by removing the 4-sulfate group at the non-reducing end of the C4S chain, but has not previously been shown to affect C4S biosynthesis. The decline in CHST11 expression following ARSB reduction is attributable to effects of ARSB on bone morphogenetic protein (BMP)4, since BMP4 expression and secretion declined when ARSB was silenced. Inhibition of BMP4 by neutralizing antibody also reduced CHST11 expression. When C4S was more sulfated due to decline in ARSB, more BMP4 was sequestered by C4S in the cell membrane, and CHST11 expression declined. Exogenous recombinant BMP4, acting through a phospho-Smad3 binding site in the CHST11 promoter, increased the mRNA expression of CHST11. In contrast to the decline in BMP4 that followed decline in ARSB, Wnt9A mRNA expression was previously shown to increase when ARSB was silenced and C4S was more highly sulfated. Galectin-3 bound less to the more highly sulfated C4S, leading to increased nuclear translocation and enhanced galectin-3 interaction with Sp1 in the Wnt9A promoter. Silencing Wnt9A increased the expression of CHST11 in the colonic epithelial cells, and chromatin immunoprecipitation assay demonstrated enhancing effects of Wnt9A siRNA and exogenous BMP4 on the CHST11 promoter through the pSmad3 binding site. These findings suggest that cellular processes mediated by differential effects of Wnt9A and BMP4 can result from opposing effects on CHST11 expression.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States; Jesse Brown VA Medical Center, Chicago, IL 60612, United States.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States; Jesse Brown VA Medical Center, Chicago, IL 60612, United States.
authors.forename: Leo
authors.initials: L
authors.lastname: Feferman
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, United States; Jesse Brown VA Medical Center, Chicago, IL 60612, United States. Electronic address: jkt@uic.edu.
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D002809:Chondroitin Sulfates / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D037502:Galectin 3; C110670:WNT9A protein, human; D051153:Wnt Proteins; D002809:Chondroitin Sulfates; C411659:CHST11 protein, human; D015238:Sulfotransferases; D020051:N-Acetylgalactosamine-4-Sulfatase; C581941:ARSB protein, human
keywords: Arylsulfatase B; BMP; Chondroitin; Sulfatase; Sulfotransferase; Wnt