Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans
The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 f...
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| description | The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB-PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB-PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program. |
| doi_str_mv | 10.1371/journal.pgen.1002972 |
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As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB-PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB-PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1002972</identifier><identifier>PMID: 23028371</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Binding Sites ; Biology ; CCCTC-Binding Factor ; Cell adhesion & migration ; Cockayne Syndrome - genetics ; Cockayne Syndrome - immunology ; Cockayne Syndrome - metabolism ; DNA binding proteins ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA repair ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA Transposable Elements - genetics ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Enzymes ; Gene expression ; Gene Expression Regulation - genetics ; Genetic transcription ; Genetics ; Genomes ; Health aspects ; Human genetics ; Humans ; Immunity, Innate - genetics ; Interferon ; Mutant Chimeric Proteins - genetics ; Mutant Chimeric Proteins - immunology ; Mutant Chimeric Proteins - metabolism ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Ontology ; Physiological aspects ; Poly-ADP-Ribose Binding Proteins ; Proteins ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; RNA polymerase ; TEA Domain Transcription Factors ; Transcription Factor AP-1 - genetics ; Transcription Factor AP-1 - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcriptome ; Transposons</subject><ispartof>PLoS genetics, 2012-09, Vol.8 (9), p.e1002972-e1002972</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Gray et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Gray LT, Fong KK, Pavelitz T, Weiner AM (2012) Tethering of the Conserved piggyBac Transposase Fusion Protein CSB-PGBD3 to Chromosomal AP-1 Proteins Regulates Expression of Nearby Genes in Humans. PLoS Genet 8(9): e1002972. doi:10.1371/journal.pgen.1002972</rights><rights>2012 Gray et al 2012 Gray et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-5f507aebcbd1868711eda3cb9771ffc69f01f0bc202832502dd961091b48f25d3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459987/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459987/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23028371$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Barsh, Gregory S.</contributor><creatorcontrib>Gray, Lucas T</creatorcontrib><creatorcontrib>Fong, Kimberly K</creatorcontrib><creatorcontrib>Pavelitz, Thomas</creatorcontrib><creatorcontrib>Weiner, Alan M</creatorcontrib><title>Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB-PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB-PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program.</description><subject>Angiogenesis</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>CCCTC-Binding Factor</subject><subject>Cell adhesion & migration</subject><subject>Cockayne Syndrome - genetics</subject><subject>Cockayne Syndrome - immunology</subject><subject>Cockayne Syndrome - metabolism</subject><subject>DNA binding proteins</subject><subject>DNA Helicases - genetics</subject><subject>DNA Helicases - metabolism</subject><subject>DNA repair</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA Transposable Elements - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - genetics</subject><subject>Genetic transcription</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Human genetics</subject><subject>Humans</subject><subject>Immunity, Innate - genetics</subject><subject>Interferon</subject><subject>Mutant Chimeric Proteins - genetics</subject><subject>Mutant Chimeric Proteins - immunology</subject><subject>Mutant Chimeric Proteins - metabolism</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Ontology</subject><subject>Physiological aspects</subject><subject>Poly-ADP-Ribose Binding Proteins</subject><subject>Proteins</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA polymerase</subject><subject>TEA Domain Transcription Factors</subject><subject>Transcription Factor AP-1 - 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genetics</topic><topic>Cockayne Syndrome - immunology</topic><topic>Cockayne Syndrome - metabolism</topic><topic>DNA binding proteins</topic><topic>DNA Helicases - genetics</topic><topic>DNA Helicases - metabolism</topic><topic>DNA repair</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>DNA Transposable Elements - genetics</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enzymes</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - genetics</topic><topic>Genetic transcription</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Health aspects</topic><topic>Human genetics</topic><topic>Humans</topic><topic>Immunity, Innate - genetics</topic><topic>Interferon</topic><topic>Mutant Chimeric Proteins - genetics</topic><topic>Mutant Chimeric Proteins - immunology</topic><topic>Mutant Chimeric Proteins - metabolism</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gray, Lucas T</au><au>Fong, Kimberly K</au><au>Pavelitz, Thomas</au><au>Weiner, Alan M</au><au>Barsh, Gregory S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>8</volume><issue>9</issue><spage>e1002972</spage><epage>e1002972</epage><pages>e1002972-e1002972</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>The CSB-PGBD3 fusion protein arose more than 43 million years ago when a 2.5-kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. As a result, full-length CSB is now coexpressed with an abundant CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1-5 to the PGBD3 transposase. An internal deletion of the piggyBac transposase ORF also gave rise to 889 dispersed, 140-bp MER85 elements that were mobilized in trans by PGBD3 transposase. The CSB-PGBD3 fusion protein binds MER85s in vitro and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. CSB-PGBD3 binds to 363 MER85 elements in vivo, but these sites do not correlate with gene expression changes induced by the fusion protein. Instead, CSB-PGBD3 is enriched at AP-1, TEAD1, and CTCF motifs, presumably through protein-protein interactions with the cognate transcription factors; moreover, recruitment of CSB-PGBD3 to AP-1 and TEAD1 motifs correlates with nearby genes regulated by CSB-PGBD3 expression in UVSS1KO cells and downregulated by CSB rescue of mutant CS1AN cells. Consistent with these data, the N-terminal CSB domain of the CSB-PGBD3 fusion protein interacts with the AP-1 transcription factor c-Jun and with RNA polymerase II, and a chimeric CSB-LacI construct containing only the N-terminus of CSB upregulates many of the genes induced by CSB-PGBD3. We conclude that the CSB-PGBD3 fusion protein substantially reshapes the transcriptome in CS patient CS1AN and that continued expression of the CSB-PGBD3 fusion protein in the absence of functional CSB may affect the clinical presentation of CS patients by directly altering the transcriptional program.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23028371</pmid><doi>10.1371/journal.pgen.1002972</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis Binding Sites Biology CCCTC-Binding Factor Cell adhesion & migration Cockayne Syndrome - genetics Cockayne Syndrome - immunology Cockayne Syndrome - metabolism DNA binding proteins DNA Helicases - genetics DNA Helicases - metabolism DNA repair DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA Transposable Elements - genetics DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Enzymes Gene expression Gene Expression Regulation - genetics Genetic transcription Genetics Genomes Health aspects Human genetics Humans Immunity, Innate - genetics Interferon Mutant Chimeric Proteins - genetics Mutant Chimeric Proteins - immunology Mutant Chimeric Proteins - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Ontology Physiological aspects Poly-ADP-Ribose Binding Proteins Proteins Repressor Proteins - genetics Repressor Proteins - metabolism RNA polymerase TEA Domain Transcription Factors Transcription Factor AP-1 - genetics Transcription Factor AP-1 - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transcriptome Transposons |
| title | Tethering of the conserved piggyBac transposase fusion protein CSB-PGBD3 to chromosomal AP-1 proteins regulates expression of nearby genes in humans |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-11T00%3A42%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tethering%20of%20the%20conserved%20piggyBac%20transposase%20fusion%20protein%20CSB-PGBD3%20to%20chromosomal%20AP-1%20proteins%20regulates%20expression%20of%20nearby%20genes%20in%20humans&rft.jtitle=PLoS%20genetics&rft.au=Gray,%20Lucas%20T&rft.date=2012-09-01&rft.volume=8&rft.issue=9&rft.spage=e1002972&rft.epage=e1002972&rft.pages=e1002972-e1002972&rft.issn=1553-7404&rft.eissn=1553-7404&rft_id=info:doi/10.1371/journal.pgen.1002972&rft_dat=%3Cgale_plos_%3EA305191927%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1313540790&rft_id=info:pmid/23028371&rft_galeid=A305191927&rft_doaj_id=oai_doaj_org_article_c945c18cde3f4cd48feae247565eb367&rfr_iscdi=true |