Regulatory Gene Mutations Affecting Apolipoprotein Gene Expression: Functions and Regulatory Behavior of Known Genes May Guide Future Pharmacogenomic Approaches to Therapy

Regulatory Gene Mutations Affecting Apolipoprotein Gene Expression: Functions and Regulatory... Abstract A pharmacogenomic approach to therapy requires systematic knowledge of the regulatory regions of the genes, as well as basic understanding of transcriptional regulatory mechanisms of genes. Using the apolipoprotein (apo) A-I/CIII gene cluster as a model system, we have identified by in vitro and in vivo studies the regulatory elements and the factors which control its transcription. Studies in transgenic mice established that the hepatocyte nuclear factor (HNF-4) binding site of the apoCIII enhancer, which controls transcription of both genes, is required for the intestinal expression of apoA-I and apoCIII genes, and enhances synergistically their hepatic transcription in vivo . The three Sp1 sites of the enhancer are also required for the intestinal expression of apoA-I and apoCIII genes in vivo, and for the enhancement of the hepatic transcription. The regulation of the apoE/apoCI/apoCIV/apoCII cluster is also cited. It is expected that identification of the regulatory regions of genes will be soon accelerated by the sequencing of several mammalian genomes. The functional analyses of the regulatory domains of genes involved in lipid homeostasis, combined with cross-species sequence comparisons in the near future, may identify natural regulatory gene polymorphisms in the general population that will permit rational pharmacogenomic approaches for treatment of dyslipidemias. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Chemistry and Laboratory Medicine (CCLM) de Gruyter

Regulatory Gene Mutations Affecting Apolipoprotein Gene Expression: Functions and Regulatory Behavior of Known Genes May Guide Future Pharmacogenomic Approaches to Therapy

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Publisher
de Gruyter
Copyright
Copyright © 2003 by the
ISSN
1434-6621
DOI
10.1515/CCLM.2003.064
pmid
12747582
Publisher site
See Article on Publisher Site

Abstract

Abstract A pharmacogenomic approach to therapy requires systematic knowledge of the regulatory regions of the genes, as well as basic understanding of transcriptional regulatory mechanisms of genes. Using the apolipoprotein (apo) A-I/CIII gene cluster as a model system, we have identified by in vitro and in vivo studies the regulatory elements and the factors which control its transcription. Studies in transgenic mice established that the hepatocyte nuclear factor (HNF-4) binding site of the apoCIII enhancer, which controls transcription of both genes, is required for the intestinal expression of apoA-I and apoCIII genes, and enhances synergistically their hepatic transcription in vivo . The three Sp1 sites of the enhancer are also required for the intestinal expression of apoA-I and apoCIII genes in vivo, and for the enhancement of the hepatic transcription. The regulation of the apoE/apoCI/apoCIV/apoCII cluster is also cited. It is expected that identification of the regulatory regions of genes will be soon accelerated by the sequencing of several mammalian genomes. The functional analyses of the regulatory domains of genes involved in lipid homeostasis, combined with cross-species sequence comparisons in the near future, may identify natural regulatory gene polymorphisms in the general population that will permit rational pharmacogenomic approaches for treatment of dyslipidemias.

Journal

Clinical Chemistry and Laboratory Medicine (CCLM)de Gruyter

Published: Apr 25, 2003

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