Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2

ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL...

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Veröffentlicht in:Biochimica et biophysica acta 2014-06, Vol.1839 (6), p.526-536
Hauptverfasser: Thymiakou, Efstathia, Kardassis, Dimitris
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description ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. [Display omitted] •Τranscription factor FOXA2 is a negative modulator of ABCA1 gene in hepatic cells.•Inhibition of FOXA2 is associated with increased ABCA1 promoter activity and protein levels.•The ABCA1 promoter contains three FOXA2 binding elements in the proximal region.•One of the FOXA2 sites is the core of the TATA element of the ABCA1 promoter.•Overexpression of FOXA2 inhibited ABCA1 gene induction by the oxysterol/LXR pathway.
doi_str_mv 10.1016/j.bbagrm.2014.04.021
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Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. 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Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. 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Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. [Display omitted] •Τranscription factor FOXA2 is a negative modulator of ABCA1 gene in hepatic cells.•Inhibition of FOXA2 is associated with increased ABCA1 promoter activity and protein levels.•The ABCA1 promoter contains three FOXA2 binding elements in the proximal region.•One of the FOXA2 sites is the core of the TATA element of the ABCA1 promoter.•Overexpression of FOXA2 inhibited ABCA1 gene induction by the oxysterol/LXR pathway.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>24807696</pmid><doi>10.1016/j.bbagrm.2014.04.021</doi><tpages>11</tpages></addata></record>
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subjects ABCA1
ATP Binding Cassette Transporter 1 - genetics
ATP Binding Cassette Transporter 1 - metabolism
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Cells, Cultured
Chromatin Immunoprecipitation
Fluorescent Antibody Technique, Indirect
FOXA2
Gene Expression Regulation - drug effects
HEK293 Cells
Hepatocyte Nuclear Factor 3-beta - genetics
Hepatocyte Nuclear Factor 3-beta - metabolism
Humans
Hydroxycholesterols - pharmacology
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Promoter Regions, Genetic - genetics
Real-Time Polymerase Chain Reaction
Retinoids - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
TATA box
Transcription, Genetic - drug effects
Transcriptional repression
title Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2
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