Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism

FRA-2/FOSL2 is a basic region-leucine zipper motif transcription factor that is widely expressed in mammalian tissues. The functional repertoire of this factor is unclear, partly due to a lack of knowledge of genomic sequences that are targeted. Here, we identified novel, functional FRA-2 targets ac...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2011-04, Vol.286 (17), p.15227-15239
Hauptverfasser: Davies, Jeff S, Klein, David C, Carter, David A
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 15239
container_issue 17
container_start_page 15227
container_title The Journal of biological chemistry
container_volume 286
creator Davies, Jeff S
Klein, David C
Carter, David A
description FRA-2/FOSL2 is a basic region-leucine zipper motif transcription factor that is widely expressed in mammalian tissues. The functional repertoire of this factor is unclear, partly due to a lack of knowledge of genomic sequences that are targeted. Here, we identified novel, functional FRA-2 targets across the genome through expression profile analysis in a knockdown transgenic rat. In this model, a nocturnal rhythm of pineal gland FRA-2 is suppressed by a genetically encoded, dominant negative mutant protein. Bioinformatic analysis of validated sets of FRA-2-regulated and -nonregulated genes revealed that the FRA-2 regulon is limited by genomic target selection rules that, in general, transcend core cis-sequence identity. However, one variant AP-1-related (AP-1R) sequence was common to a subset of regulated genes. The functional activity and protein binding partners of a candidate AP-1R sequence were determined for a novel FRA-2-repressed gene, Rgs4. FRA-2 protein preferentially associated with a proximal Rgs4 AP-1R sequence as demonstrated by ex vivo ChIP and in vitro EMSA analysis; moreover, transcriptional repression was blocked by mutation of the AP-1R sequence, whereas mutation of an upstream consensus AP-1 family sequence did not affect Rgs4 expression. Nocturnal changes in protein complexes at the Rgs4 AP-1R sequence are associated with FRA-2-dependent dismissal of the co-activator, CBP; this provides a mechanistic basis for Rgs4 gene repression. These studies have also provided functional insight into selective genomic targeting by FRA-2, highlighting discordance between predicted and actual targets. Future studies should address FRA-2-Rgs4 interactions in other systems, including the brain, where FRA-2 function is poorly understood.
doi_str_mv 10.1074/jbc.M110.201996
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_863433266</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>863433266</sourcerecordid><originalsourceid>FETCH-LOGICAL-p210t-37e856e27031722b7958fca57b7851f3ebfa2726542ccac99ac2a44f663bbe453</originalsourceid><addsrcrecordid>eNo1kE1P4zAQhi2kFbCFMzfk28IhNP5InOytVBSQikBlV-JWjd1JMEqcru0i8Qv3b-HwMZfRvHrnmVdDyAnLL1iu5PRFm4s7liaes7ou98ghyyuRiYI9HZCfIbzkqWTN9skBZ6JUVSkPyf9H7NBE-4q0RTf01tAIvsVoXUv1G12sZhmfLu4fl5xGDy4Yb7fRDo42YOLgf1OP7a6DD2loaHxGumqDHGlIbaA9bixE3IwwoK_gLbhIYTwJaZ9u_RDROsro2ewhY-ej0CfJ04D_dugMTuerq8tMW7cZM337z-aXD-eJbp7B2dAfkR8NdAGPv_qE_F1c_ZnfZMv769v5bJltOctjJhRWRYlc5YIpzrWqi6oxUCitqoI1AnUDXPGykNwYMHUNhoOUTVkKrVEWYkJ-fXJTjhQvxHVvg8GuA4fDLqyrUkghePJPyOmXc6fTE9Zbb3vwb-vv34t35MmFpA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>863433266</pqid></control><display><type>article</type><title>Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Davies, Jeff S ; Klein, David C ; Carter, David A</creator><creatorcontrib>Davies, Jeff S ; Klein, David C ; Carter, David A</creatorcontrib><description>FRA-2/FOSL2 is a basic region-leucine zipper motif transcription factor that is widely expressed in mammalian tissues. The functional repertoire of this factor is unclear, partly due to a lack of knowledge of genomic sequences that are targeted. Here, we identified novel, functional FRA-2 targets across the genome through expression profile analysis in a knockdown transgenic rat. In this model, a nocturnal rhythm of pineal gland FRA-2 is suppressed by a genetically encoded, dominant negative mutant protein. Bioinformatic analysis of validated sets of FRA-2-regulated and -nonregulated genes revealed that the FRA-2 regulon is limited by genomic target selection rules that, in general, transcend core cis-sequence identity. However, one variant AP-1-related (AP-1R) sequence was common to a subset of regulated genes. The functional activity and protein binding partners of a candidate AP-1R sequence were determined for a novel FRA-2-repressed gene, Rgs4. FRA-2 protein preferentially associated with a proximal Rgs4 AP-1R sequence as demonstrated by ex vivo ChIP and in vitro EMSA analysis; moreover, transcriptional repression was blocked by mutation of the AP-1R sequence, whereas mutation of an upstream consensus AP-1 family sequence did not affect Rgs4 expression. Nocturnal changes in protein complexes at the Rgs4 AP-1R sequence are associated with FRA-2-dependent dismissal of the co-activator, CBP; this provides a mechanistic basis for Rgs4 gene repression. These studies have also provided functional insight into selective genomic targeting by FRA-2, highlighting discordance between predicted and actual targets. Future studies should address FRA-2-Rgs4 interactions in other systems, including the brain, where FRA-2 function is poorly understood.</description><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.201996</identifier><identifier>PMID: 21367864</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Circadian Rhythm - genetics ; CREB-Binding Protein - metabolism ; Fos-Related Antigen-2 - genetics ; Gene Expression Regulation - physiology ; Genetic Variation ; Genome ; Promoter Regions, Genetic ; Rats ; Rats, Transgenic ; RGS Proteins - genetics ; Transcription Factor AP-1 - genetics</subject><ispartof>The Journal of biological chemistry, 2011-04, Vol.286 (17), p.15227-15239</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21367864$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Davies, Jeff S</creatorcontrib><creatorcontrib>Klein, David C</creatorcontrib><creatorcontrib>Carter, David A</creatorcontrib><title>Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>FRA-2/FOSL2 is a basic region-leucine zipper motif transcription factor that is widely expressed in mammalian tissues. The functional repertoire of this factor is unclear, partly due to a lack of knowledge of genomic sequences that are targeted. Here, we identified novel, functional FRA-2 targets across the genome through expression profile analysis in a knockdown transgenic rat. In this model, a nocturnal rhythm of pineal gland FRA-2 is suppressed by a genetically encoded, dominant negative mutant protein. Bioinformatic analysis of validated sets of FRA-2-regulated and -nonregulated genes revealed that the FRA-2 regulon is limited by genomic target selection rules that, in general, transcend core cis-sequence identity. However, one variant AP-1-related (AP-1R) sequence was common to a subset of regulated genes. The functional activity and protein binding partners of a candidate AP-1R sequence were determined for a novel FRA-2-repressed gene, Rgs4. FRA-2 protein preferentially associated with a proximal Rgs4 AP-1R sequence as demonstrated by ex vivo ChIP and in vitro EMSA analysis; moreover, transcriptional repression was blocked by mutation of the AP-1R sequence, whereas mutation of an upstream consensus AP-1 family sequence did not affect Rgs4 expression. Nocturnal changes in protein complexes at the Rgs4 AP-1R sequence are associated with FRA-2-dependent dismissal of the co-activator, CBP; this provides a mechanistic basis for Rgs4 gene repression. These studies have also provided functional insight into selective genomic targeting by FRA-2, highlighting discordance between predicted and actual targets. Future studies should address FRA-2-Rgs4 interactions in other systems, including the brain, where FRA-2 function is poorly understood.</description><subject>Animals</subject><subject>Circadian Rhythm - genetics</subject><subject>CREB-Binding Protein - metabolism</subject><subject>Fos-Related Antigen-2 - genetics</subject><subject>Gene Expression Regulation - physiology</subject><subject>Genetic Variation</subject><subject>Genome</subject><subject>Promoter Regions, Genetic</subject><subject>Rats</subject><subject>Rats, Transgenic</subject><subject>RGS Proteins - genetics</subject><subject>Transcription Factor AP-1 - genetics</subject><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kE1P4zAQhi2kFbCFMzfk28IhNP5InOytVBSQikBlV-JWjd1JMEqcru0i8Qv3b-HwMZfRvHrnmVdDyAnLL1iu5PRFm4s7liaes7ou98ghyyuRiYI9HZCfIbzkqWTN9skBZ6JUVSkPyf9H7NBE-4q0RTf01tAIvsVoXUv1G12sZhmfLu4fl5xGDy4Yb7fRDo42YOLgf1OP7a6DD2loaHxGumqDHGlIbaA9bixE3IwwoK_gLbhIYTwJaZ9u_RDROsro2ewhY-ej0CfJ04D_dugMTuerq8tMW7cZM337z-aXD-eJbp7B2dAfkR8NdAGPv_qE_F1c_ZnfZMv769v5bJltOctjJhRWRYlc5YIpzrWqi6oxUCitqoI1AnUDXPGykNwYMHUNhoOUTVkKrVEWYkJ-fXJTjhQvxHVvg8GuA4fDLqyrUkghePJPyOmXc6fTE9Zbb3vwb-vv34t35MmFpA</recordid><startdate>20110429</startdate><enddate>20110429</enddate><creator>Davies, Jeff S</creator><creator>Klein, David C</creator><creator>Carter, David A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20110429</creationdate><title>Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism</title><author>Davies, Jeff S ; Klein, David C ; Carter, David A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p210t-37e856e27031722b7958fca57b7851f3ebfa2726542ccac99ac2a44f663bbe453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Circadian Rhythm - genetics</topic><topic>CREB-Binding Protein - metabolism</topic><topic>Fos-Related Antigen-2 - genetics</topic><topic>Gene Expression Regulation - physiology</topic><topic>Genetic Variation</topic><topic>Genome</topic><topic>Promoter Regions, Genetic</topic><topic>Rats</topic><topic>Rats, Transgenic</topic><topic>RGS Proteins - genetics</topic><topic>Transcription Factor AP-1 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Davies, Jeff S</creatorcontrib><creatorcontrib>Klein, David C</creatorcontrib><creatorcontrib>Carter, David A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davies, Jeff S</au><au>Klein, David C</au><au>Carter, David A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-04-29</date><risdate>2011</risdate><volume>286</volume><issue>17</issue><spage>15227</spage><epage>15239</epage><pages>15227-15239</pages><eissn>1083-351X</eissn><abstract>FRA-2/FOSL2 is a basic region-leucine zipper motif transcription factor that is widely expressed in mammalian tissues. The functional repertoire of this factor is unclear, partly due to a lack of knowledge of genomic sequences that are targeted. Here, we identified novel, functional FRA-2 targets across the genome through expression profile analysis in a knockdown transgenic rat. In this model, a nocturnal rhythm of pineal gland FRA-2 is suppressed by a genetically encoded, dominant negative mutant protein. Bioinformatic analysis of validated sets of FRA-2-regulated and -nonregulated genes revealed that the FRA-2 regulon is limited by genomic target selection rules that, in general, transcend core cis-sequence identity. However, one variant AP-1-related (AP-1R) sequence was common to a subset of regulated genes. The functional activity and protein binding partners of a candidate AP-1R sequence were determined for a novel FRA-2-repressed gene, Rgs4. FRA-2 protein preferentially associated with a proximal Rgs4 AP-1R sequence as demonstrated by ex vivo ChIP and in vitro EMSA analysis; moreover, transcriptional repression was blocked by mutation of the AP-1R sequence, whereas mutation of an upstream consensus AP-1 family sequence did not affect Rgs4 expression. Nocturnal changes in protein complexes at the Rgs4 AP-1R sequence are associated with FRA-2-dependent dismissal of the co-activator, CBP; this provides a mechanistic basis for Rgs4 gene repression. These studies have also provided functional insight into selective genomic targeting by FRA-2, highlighting discordance between predicted and actual targets. Future studies should address FRA-2-Rgs4 interactions in other systems, including the brain, where FRA-2 function is poorly understood.</abstract><cop>United States</cop><pmid>21367864</pmid><doi>10.1074/jbc.M110.201996</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier EISSN: 1083-351X
ispartof The Journal of biological chemistry, 2011-04, Vol.286 (17), p.15227-15239
issn 1083-351X
language eng
recordid cdi_proquest_miscellaneous_863433266
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection
subjects Animals
Circadian Rhythm - genetics
CREB-Binding Protein - metabolism
Fos-Related Antigen-2 - genetics
Gene Expression Regulation - physiology
Genetic Variation
Genome
Promoter Regions, Genetic
Rats
Rats, Transgenic
RGS Proteins - genetics
Transcription Factor AP-1 - genetics
title Selective genomic targeting by FRA-2/FOSL2 transcription factor: regulation of the Rgs4 gene is mediated by a variant activator protein 1 (AP-1) promoter sequence/CREB-binding protein (CBP) mechanism
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T18%3A51%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Selective%20genomic%20targeting%20by%20FRA-2/FOSL2%20transcription%20factor:%20regulation%20of%20the%20Rgs4%20gene%20is%20mediated%20by%20a%20variant%20activator%20protein%201%20(AP-1)%20promoter%20sequence/CREB-binding%20protein%20(CBP)%20mechanism&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Davies,%20Jeff%20S&rft.date=2011-04-29&rft.volume=286&rft.issue=17&rft.spage=15227&rft.epage=15239&rft.pages=15227-15239&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M110.201996&rft_dat=%3Cproquest_pubme%3E863433266%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=863433266&rft_id=info:pmid/21367864&rfr_iscdi=true