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...
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Veröffentlicht in: | The Journal of biological chemistry 2011-04, Vol.286 (17), p.15227-15239 |
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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 |
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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> |
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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 |
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