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Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene.

ABSTRACT: Mucin glycan is the primary determinant of mucin functions. These functions are expanded by three branch structures, including core 2, core 4, and blood group I, which are synthesized by core 2 beta1,6 N-acetylglucosaminyltransferase-M (C2GnT-M). Alteration of C2GnT-M gene expression is expected to have a profound effect on mucin functions, which prompted us to study the regulation of this gene. Quantitative real-time PCR analysis of the expression of this gene in 24 human tissues and airway epithelial cells showed that this gene was expressed primarily in mucus-secretory tissues. 5' Rapid amplification of cDNA ends analysis, coupled with sequence alignment with human genome database, revealed that this gene was comprised of three exons and two introns. Northern blotting using exon 1 probe showed the presence of this exon in all transcripts, suggesting the presence of cis-regulatory elements in the proximal region upstream of and/or near the transcription initiation site (+1). Analysis of this DNA region (-417/+187) by a promoter-reporter transient transfection assay, coupled with serial deletion and linker scanning mutagenesis, revealed two positive regulatory regions, including -291/-282, and -62/-43. Further, the promoter activity was enhanced by all-trans retinoic acid (ATRA) and IL-13. Thus, the promoter region is specific to hC2GnT-M gene and subject to regulation by ATRA and IL-13. These cis-regulatory elements may be useful for construction of a mucus cell-specific vector for therapy of mucus hypersecretory diseases.

SUBMITTER: Tan S

PROVIDER: S-EPMC1899342 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene.

Tan Shuhua S Cheng Pi-Wan PW

American journal of respiratory cell and molecular biology 20070215 6

Mucin glycan is the primary determinant of mucin functions. These functions are expanded by three branch structures, including core 2, core 4, and blood group I, which are synthesized by core 2 beta1,6 N-acetylglucosaminyltransferase-M (C2GnT-M). Alteration of C2GnT-M gene expression is expected to have a profound effect on mucin functions, which prompted us to study the regulation of this gene. Quantitative real-time PCR analysis of the expression of this gene in 24 human tissues and airway epi ...[more]

PMID: 17303715

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Project description:BackgroundCardiomyopathies, degenerative diseases of cardiac muscle, are among the leading causes of death in the developed world. Microarray studies of cardiomyopathies have identified up to several hundred genes that significantly alter their expression patterns as the disease progresses. However, the regulatory mechanisms driving these changes, in particular the networks of transcription factors involved, remain poorly understood. Our goals are (A) to identify modules of co-regulated genes that undergo similar changes in expression in various types of cardiomyopathies, and (B) to reveal the specific pattern of transcription factor binding sites, cis-elements, in the proximal promoter region of genes comprising such modules.MethodsWe analyzed 149 microarray samples from human hypertrophic and dilated cardiomyopathies of various etiologies. Hierarchical clustering and Gene Ontology annotations were applied to identify modules enriched in genes with highly correlated expression and a similar physiological function. To discover motifs that may underly changes in expression, we used the promoter regions for genes in three of the most interesting modules as input to motif discovery algorithms. The resulting motifs were used to construct a probabilistic model predictive of changes in expression across different cardiomyopathies.ResultsWe found that three modules with the highest degree of functional enrichment contain genes involved in myocardial contraction (n = 9), energy generation (n = 20), or protein translation (n = 20). Using motif discovery tools revealed that genes in the contractile module were found to contain a TATA-box followed by a CACC-box, and are depleted in other GC-rich motifs; whereas genes in the translation module contain a pyrimidine-rich initiator, Elk-1, SP-1, and a novel motif with a GCGC core. Using a naïve Bayes classifier revealed that patterns of motifs are statistically predictive of expression patterns, with odds ratios of 2.7 (contractile), 1.9 (energy generation), and 5.5 (protein translation).ConclusionWe identified patterns comprised of putative cis-regulatory motifs enriched in the upstream promoter sequence of genes that undergo similar changes in expression secondary to cardiomyopathies of various etiologies. Our analysis is a first step towards understanding transcription factor networks that are active in regulating gene expression during degenerative heart disease.

Dataset Information

Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene.

Publications

Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene.

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