Multiple retinoic acid response elements cooperate to enhance the inducibility of CYP26A1 gene expression in liver

Yao Zhang, R. Zolfaghari Reza, A. Catharine Ross

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

CYP26A1, which catalyzes the oxidation of all-trans (at)-retinoic acid (RA), is induced moderately by RA in numerous tissues, but is highly responsive in liver. To understand this difference, we have examined the CYP26A1 gene sequence, identified multiple RA response elements (RAREs) and tested them functionally in HepG2 cells as model hepatocytes, and in the liver of vitamin A (VA)-adequate and -deficient rats. Analysis of a 2.2. kbp 5'-flanking region upstream of the CYP26A1 transcription start site (TSS) identified 3 conserved hexameric direct repeat-5 elements, RARE1, -2 and -3, and a half site, RARE4. The full-length promoter containing all 4 elements was sufficient and necessary to increase promoter activity similar to levels of endogenous CYP26A1 mRNA produced in HepG2 cells treated with at-RA. In DNA binding and chromatin immunoprecipitation assays, the binding of RARs to the proximal RARE1 and distal RARE2, -3, and -4 regions of the CYP26A1 promoter was increased in RA-treated HepG2 cells, and greater in VA-sufficient than VA-deficient liver. Moreover, RA increased the binding of RNA polymerase-II in the distal as well as the proximal region, indicating that the distal region may be looped to become positioned close to the TSS, a process favored by retinoic acid receptors. The results support a cooperative model in which the functioning of multiple RAREs may account for the strong inducibility of CYP26A1 in liver, which, in turn, may be important physiologically for restoring retinoid homeostasis when the concentration of RA rises.

Original languageEnglish (US)
Pages (from-to)32-43
Number of pages12
JournalGene
Volume464
Issue number1-2
DOIs
StatePublished - Sep 1 2010

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Response Elements
Tretinoin
Gene Expression
Liver
Hep G2 Cells
Vitamin A
Transcription Initiation Site
Retinoic Acid Receptors
RNA Polymerase II
Nucleic Acid Repetitive Sequences
Chromatin Immunoprecipitation
5' Flanking Region
Retinoids
Retinoic Acid 4-Hydroxylase
Genetic Promoter Regions
Hepatocytes
Homeostasis
Messenger RNA
DNA
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

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title = "Multiple retinoic acid response elements cooperate to enhance the inducibility of CYP26A1 gene expression in liver",
abstract = "CYP26A1, which catalyzes the oxidation of all-trans (at)-retinoic acid (RA), is induced moderately by RA in numerous tissues, but is highly responsive in liver. To understand this difference, we have examined the CYP26A1 gene sequence, identified multiple RA response elements (RAREs) and tested them functionally in HepG2 cells as model hepatocytes, and in the liver of vitamin A (VA)-adequate and -deficient rats. Analysis of a 2.2. kbp 5'-flanking region upstream of the CYP26A1 transcription start site (TSS) identified 3 conserved hexameric direct repeat-5 elements, RARE1, -2 and -3, and a half site, RARE4. The full-length promoter containing all 4 elements was sufficient and necessary to increase promoter activity similar to levels of endogenous CYP26A1 mRNA produced in HepG2 cells treated with at-RA. In DNA binding and chromatin immunoprecipitation assays, the binding of RARs to the proximal RARE1 and distal RARE2, -3, and -4 regions of the CYP26A1 promoter was increased in RA-treated HepG2 cells, and greater in VA-sufficient than VA-deficient liver. Moreover, RA increased the binding of RNA polymerase-II in the distal as well as the proximal region, indicating that the distal region may be looped to become positioned close to the TSS, a process favored by retinoic acid receptors. The results support a cooperative model in which the functioning of multiple RAREs may account for the strong inducibility of CYP26A1 in liver, which, in turn, may be important physiologically for restoring retinoid homeostasis when the concentration of RA rises.",
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Multiple retinoic acid response elements cooperate to enhance the inducibility of CYP26A1 gene expression in liver. / Zhang, Yao; Zolfaghari Reza, R.; Ross, A. Catharine.

In: Gene, Vol. 464, No. 1-2, 01.09.2010, p. 32-43.

Research output: Contribution to journalArticle

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