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...
Gespeichert in:
Veröffentlicht in: | Biochimica et biophysica acta 2014-06, Vol.1839 (6), p.526-536 |
---|---|
Hauptverfasser: | , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 536 |
---|---|
container_issue | 6 |
container_start_page | 526 |
container_title | Biochimica et biophysica acta |
container_volume | 1839 |
creator | Thymiakou, Efstathia Kardassis, Dimitris |
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 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1540225902</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1874939914001047</els_id><sourcerecordid>1540225902</sourcerecordid><originalsourceid>FETCH-LOGICAL-c395t-42e8a37f73cc7b3e6a76eb3d9b5626f5a88d41d00d9f55c3ea7ba7899884f0043</originalsourceid><addsrcrecordid>eNp9UcluFDEQbSEQCYE_QMhHLj3x1osvSKMoLFIEHMLZ8lI97aHbbmxPSD6Kf8QzHZC4IJVUVar3XlXpVdVrgjcEk_Zyv9Fa7eK8oZjwDS5ByZPqnPRdW3NG8dNTzWvBhDirXqS0x7glFOPn1RnlPe5a0Z5Xvz6HO5jQDGZU3qUZhQHlqHwy0S3ZBa8mFGGJkFJpTtMR0HiYlUfb269IO2-d3yGjUoKcYSUvIWaIaEvQDjwg59EIi8rOIAPTlJB-OMn8LEywZTa5-8shxO8jKIt0uP_3BDQok0ORoy-rZ4OaErx6zBfVt_fXt1cf65svHz5dbW9qw0STa06hV6wbOmZMpxm0qmtBMyt009J2aFTfW04sxlYMTWMYqE6rrhei7_mAMWcX1dtVd4nhxwFSlrNLx9OVh3BIkjQcU9oITAuUr1ATQ0oRBrlEN6v4IAmWR6PkXq5GyaNREpegpNDePG446BnsX9IfZwrg3QqA8uedgyiTceANWBfBZGmD-_-G37EoqYQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1540225902</pqid></control><display><type>article</type><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</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Thymiakou, Efstathia ; Kardassis, Dimitris</creator><creatorcontrib>Thymiakou, Efstathia ; Kardassis, Dimitris</creatorcontrib><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.</description><identifier>ISSN: 1874-9399</identifier><identifier>ISSN: 0006-3002</identifier><identifier>EISSN: 1876-4320</identifier><identifier>DOI: 10.1016/j.bbagrm.2014.04.021</identifier><identifier>PMID: 24807696</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>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</subject><ispartof>Biochimica et biophysica acta, 2014-06, Vol.1839 (6), p.526-536</ispartof><rights>2014 Elsevier B.V.</rights><rights>Copyright © 2014 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c395t-42e8a37f73cc7b3e6a76eb3d9b5626f5a88d41d00d9f55c3ea7ba7899884f0043</citedby><cites>FETCH-LOGICAL-c395t-42e8a37f73cc7b3e6a76eb3d9b5626f5a88d41d00d9f55c3ea7ba7899884f0043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1874939914001047$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24807696$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thymiakou, Efstathia</creatorcontrib><creatorcontrib>Kardassis, Dimitris</creatorcontrib><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</title><title>Biochimica et biophysica acta</title><addtitle>Biochim Biophys Acta</addtitle><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.</description><subject>ABCA1</subject><subject>ATP Binding Cassette Transporter 1 - genetics</subject><subject>ATP Binding Cassette Transporter 1 - metabolism</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cells, Cultured</subject><subject>Chromatin Immunoprecipitation</subject><subject>Fluorescent Antibody Technique, Indirect</subject><subject>FOXA2</subject><subject>Gene Expression Regulation - drug effects</subject><subject>HEK293 Cells</subject><subject>Hepatocyte Nuclear Factor 3-beta - genetics</subject><subject>Hepatocyte Nuclear Factor 3-beta - metabolism</subject><subject>Humans</subject><subject>Hydroxycholesterols - pharmacology</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Retinoids - pharmacology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>TATA box</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transcriptional repression</subject><issn>1874-9399</issn><issn>0006-3002</issn><issn>1876-4320</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcluFDEQbSEQCYE_QMhHLj3x1osvSKMoLFIEHMLZ8lI97aHbbmxPSD6Kf8QzHZC4IJVUVar3XlXpVdVrgjcEk_Zyv9Fa7eK8oZjwDS5ByZPqnPRdW3NG8dNTzWvBhDirXqS0x7glFOPn1RnlPe5a0Z5Xvz6HO5jQDGZU3qUZhQHlqHwy0S3ZBa8mFGGJkFJpTtMR0HiYlUfb269IO2-d3yGjUoKcYSUvIWaIaEvQDjwg59EIi8rOIAPTlJB-OMn8LEywZTa5-8shxO8jKIt0uP_3BDQok0ORoy-rZ4OaErx6zBfVt_fXt1cf65svHz5dbW9qw0STa06hV6wbOmZMpxm0qmtBMyt009J2aFTfW04sxlYMTWMYqE6rrhei7_mAMWcX1dtVd4nhxwFSlrNLx9OVh3BIkjQcU9oITAuUr1ATQ0oRBrlEN6v4IAmWR6PkXq5GyaNREpegpNDePG446BnsX9IfZwrg3QqA8uedgyiTceANWBfBZGmD-_-G37EoqYQ</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Thymiakou, Efstathia</creator><creator>Kardassis, Dimitris</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20140601</creationdate><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</title><author>Thymiakou, Efstathia ; Kardassis, Dimitris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c395t-42e8a37f73cc7b3e6a76eb3d9b5626f5a88d41d00d9f55c3ea7ba7899884f0043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>ABCA1</topic><topic>ATP Binding Cassette Transporter 1 - genetics</topic><topic>ATP Binding Cassette Transporter 1 - metabolism</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cells, Cultured</topic><topic>Chromatin Immunoprecipitation</topic><topic>Fluorescent Antibody Technique, Indirect</topic><topic>FOXA2</topic><topic>Gene Expression Regulation - drug effects</topic><topic>HEK293 Cells</topic><topic>Hepatocyte Nuclear Factor 3-beta - genetics</topic><topic>Hepatocyte Nuclear Factor 3-beta - metabolism</topic><topic>Humans</topic><topic>Hydroxycholesterols - pharmacology</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Retinoids - pharmacology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>TATA box</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transcriptional repression</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thymiakou, Efstathia</creatorcontrib><creatorcontrib>Kardassis, Dimitris</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Biochimica et biophysica acta</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thymiakou, Efstathia</au><au>Kardassis, Dimitris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Biochimica et biophysica acta</jtitle><addtitle>Biochim Biophys Acta</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>1839</volume><issue>6</issue><spage>526</spage><epage>536</epage><pages>526-536</pages><issn>1874-9399</issn><issn>0006-3002</issn><eissn>1876-4320</eissn><abstract>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.</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> |
fulltext | fulltext |
identifier | ISSN: 1874-9399 |
ispartof | Biochimica et biophysica acta, 2014-06, Vol.1839 (6), p.526-536 |
issn | 1874-9399 0006-3002 1876-4320 |
language | eng |
recordid | cdi_proquest_miscellaneous_1540225902 |
source | MEDLINE; Elsevier ScienceDirect Journals |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-16T15%3A35%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Novel%20mechanism%20of%20transcriptional%20repression%20of%20the%20human%20ATP%20binding%20cassette%20transporter%20A1%20gene%20in%20hepatic%20cells%20by%20the%20winged%20helix/forkhead%20box%20transcription%20factor%20A2&rft.jtitle=Biochimica%20et%20biophysica%20acta&rft.au=Thymiakou,%20Efstathia&rft.date=2014-06-01&rft.volume=1839&rft.issue=6&rft.spage=526&rft.epage=536&rft.pages=526-536&rft.issn=1874-9399&rft.eissn=1876-4320&rft_id=info:doi/10.1016/j.bbagrm.2014.04.021&rft_dat=%3Cproquest_cross%3E1540225902%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1540225902&rft_id=info:pmid/24807696&rft_els_id=S1874939914001047&rfr_iscdi=true |