Regulatory gene mutations affecting apolipoprotein gene expression: functions and regulatory behavior of known genes may guide future pharmacogenomic approaches to therapy.
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-land 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.
Section of Molecular Genetics, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. vzannis@bu.edu
Vassilis I
VI
Zannis
Tong
T
Liu
Markella
M
Zanni
Horng-Yuan
HY
Kan
Dimitris
D
Kardassis
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics*; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010597:Pharmacogenetics; D010750:Phosphoproteins / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism
D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors