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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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Formato: | Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083148/ https://www.ncbi.nlm.nih.gov/pubmed/21367864 http://dx.doi.org/10.1074/jbc.M110.201996 |
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author | Davies, Jeff S. Klein, David C. Carter, David A. |
author_facet | Davies, Jeff S. Klein, David C. Carter, David A. |
author_sort | Davies, Jeff S. |
collection | PubMed |
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. |
format | Text |
id | pubmed-3083148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-30831482011-05-05 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 Davies, Jeff S. Klein, David C. Carter, David A. J Biol Chem Gene Regulation 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. American Society for Biochemistry and Molecular Biology 2011-04-29 2011-03-02 /pmc/articles/PMC3083148/ /pubmed/21367864 http://dx.doi.org/10.1074/jbc.M110.201996 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Gene Regulation Davies, Jeff S. Klein, David C. Carter, David A. 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 | 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_full | 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_fullStr | 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_full_unstemmed | 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_short | 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_sort | 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 |
topic | Gene Regulation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083148/ https://www.ncbi.nlm.nih.gov/pubmed/21367864 http://dx.doi.org/10.1074/jbc.M110.201996 |
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