Identification and characterization of TGFβ-dependent and -independent cis-regulatory modules in the C4ST-1/CHST11 locus

C. M. Willis, J. L. Wrana, M. Klüppel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Chondroitin-4-sulfotransferase-1(C4ST-1)/carbohydrate sulfotransferase 11 (CHST11) is a Golgi-bound enzyme involved in the biosynthesis of the glycosaminoglycan chondroitin sulfate. The sulfation pattern of chondroitin is tightly regulated during development, injury and disease, with the temporal and spatial expression of chondroitin sulfotransferase genes believed to be a crucial determinant of the fine balance of chondroitin sulfation. We have previously identified mouse C4st-1 as a target gene of ligands of the TGFâ superfamily of growth factors, which could positively regulate C4st-1 expression in a number of cell types. We have also shown that a gene trap loss-of-function mutation in C4st-1 leads to severe skeletal abnormalities during mouse embryogenesis. In addition, we described a highly specific temporal and spatial expression pattern of C4st-1 during mouse embryogenesis. However, the transcriptional regulatory mechanisms that control C4st-1 gene expression remain unexplored. In order to gain knowledge on the transcriptional regulation of C4ST-1, we used a bioinformatical approach to identify conserved putative long-range cis-regulatory modules in a region of 120 kb spanning the 5′ end of the C4ST-1 gene. Luciferase reporter assays in human HEK293T and mouse NmuMG cells identified a functional C4ST-1 promoter, as well as a number of cis-regulatory modules able to positively and negatively regulate C4ST-1 expression. Moreover, we identified TGFβ-responsive regulatory modules that can function in a cell type-specific fashion. Taken together, our results identify TGFβ-dependent and -independent cis-regulatory modules of the C4ST-1 gene.

Original languageEnglish (US)
Pages (from-to)1331-1343
Number of pages13
JournalGenetics and Molecular Research
Volume8
Issue number4
DOIs
StatePublished - 2009

Keywords

  • C4ST-1
  • CHST11
  • Chondroitin sulfate
  • Cis-regulatory modules
  • Gene expression
  • TGFβ

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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