Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development

Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. P...
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Autor*in:	Thomas J. Cunningham [verfasserIn] Joseph J. Lancman [verfasserIn] Marie Berenguer [verfasserIn] P. Duc Si Dong [verfasserIn] Gregg Duester [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Übergeordnetes Werk:	In: Cell Reports - Elsevier, 2015, 23(2018), 11, Seite 3146-3151
Übergeordnetes Werk:	volume:23 ; year:2018 ; number:11 ; pages:3146-3151

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.celrep.2018.05.052

Katalog-ID:	DOAJ010721657

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allfields	10.1016/j.celrep.2018.05.052 doi (DE-627)DOAJ010721657 (DE-599)DOAJefb2be0a509b43199ea7a43d938ee017 DE-627 ger DE-627 rakwb eng QH301-705.5 Thomas J. Cunningham verfasserin aut Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish Biology (General) Joseph J. Lancman verfasserin aut Marie Berenguer verfasserin aut P. Duc Si Dong verfasserin aut Gregg Duester verfasserin aut In Cell Reports Elsevier, 2015 23(2018), 11, Seite 3146-3151 (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:23 year:2018 number:11 pages:3146-3151 https://doi.org/10.1016/j.celrep.2018.05.052 kostenfrei https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124718307988 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2018 11 3146-3151
spelling	10.1016/j.celrep.2018.05.052 doi (DE-627)DOAJ010721657 (DE-599)DOAJefb2be0a509b43199ea7a43d938ee017 DE-627 ger DE-627 rakwb eng QH301-705.5 Thomas J. Cunningham verfasserin aut Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish Biology (General) Joseph J. Lancman verfasserin aut Marie Berenguer verfasserin aut P. Duc Si Dong verfasserin aut Gregg Duester verfasserin aut In Cell Reports Elsevier, 2015 23(2018), 11, Seite 3146-3151 (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:23 year:2018 number:11 pages:3146-3151 https://doi.org/10.1016/j.celrep.2018.05.052 kostenfrei https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124718307988 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2018 11 3146-3151
allfields_unstemmed	10.1016/j.celrep.2018.05.052 doi (DE-627)DOAJ010721657 (DE-599)DOAJefb2be0a509b43199ea7a43d938ee017 DE-627 ger DE-627 rakwb eng QH301-705.5 Thomas J. Cunningham verfasserin aut Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish Biology (General) Joseph J. Lancman verfasserin aut Marie Berenguer verfasserin aut P. Duc Si Dong verfasserin aut Gregg Duester verfasserin aut In Cell Reports Elsevier, 2015 23(2018), 11, Seite 3146-3151 (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:23 year:2018 number:11 pages:3146-3151 https://doi.org/10.1016/j.celrep.2018.05.052 kostenfrei https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124718307988 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2018 11 3146-3151
allfieldsGer	10.1016/j.celrep.2018.05.052 doi (DE-627)DOAJ010721657 (DE-599)DOAJefb2be0a509b43199ea7a43d938ee017 DE-627 ger DE-627 rakwb eng QH301-705.5 Thomas J. Cunningham verfasserin aut Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish Biology (General) Joseph J. Lancman verfasserin aut Marie Berenguer verfasserin aut P. Duc Si Dong verfasserin aut Gregg Duester verfasserin aut In Cell Reports Elsevier, 2015 23(2018), 11, Seite 3146-3151 (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:23 year:2018 number:11 pages:3146-3151 https://doi.org/10.1016/j.celrep.2018.05.052 kostenfrei https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124718307988 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2018 11 3146-3151
allfieldsSound	10.1016/j.celrep.2018.05.052 doi (DE-627)DOAJ010721657 (DE-599)DOAJefb2be0a509b43199ea7a43d938ee017 DE-627 ger DE-627 rakwb eng QH301-705.5 Thomas J. Cunningham verfasserin aut Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish Biology (General) Joseph J. Lancman verfasserin aut Marie Berenguer verfasserin aut P. Duc Si Dong verfasserin aut Gregg Duester verfasserin aut In Cell Reports Elsevier, 2015 23(2018), 11, Seite 3146-3151 (DE-627)684964562 (DE-600)2649101-1 22111247 nnns volume:23 year:2018 number:11 pages:3146-3151 https://doi.org/10.1016/j.celrep.2018.05.052 kostenfrei https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 kostenfrei http://www.sciencedirect.com/science/article/pii/S2211124718307988 kostenfrei https://doaj.org/toc/2211-1247 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 23 2018 11 3146-3151
language	English
source	In Cell Reports 23(2018), 11, Seite 3146-3151 volume:23 year:2018 number:11 pages:3146-3151
sourceStr	In Cell Reports 23(2018), 11, Seite 3146-3151 volume:23 year:2018 number:11 pages:3146-3151
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Biology (General)
isfreeaccess_bool	true
container_title	Cell Reports
authorswithroles_txt_mv	Thomas J. Cunningham @@aut@@ Joseph J. Lancman @@aut@@ Marie Berenguer @@aut@@ P. Duc Si Dong @@aut@@ Gregg Duester @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	684964562
id	DOAJ010721657
language_de	englisch
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callnumber-first	Q - Science
author	Thomas J. Cunningham
spellingShingle	Thomas J. Cunningham misc QH301-705.5 misc Biology (General) Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
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topic_title	QH301-705.5 Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
topic	misc QH301-705.5 misc Biology (General)
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title	Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
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title_full	Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
author_sort	Thomas J. Cunningham
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author_browse	Thomas J. Cunningham Joseph J. Lancman Marie Berenguer P. Duc Si Dong Gregg Duester
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author-letter	Thomas J. Cunningham
doi_str_mv	10.1016/j.celrep.2018.05.052
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title_sort	genomic knockout of two presumed forelimb tbx5 enhancers reveals they are nonessential for limb development
callnumber	QH301-705.5
title_auth	Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
abstract	Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish
abstractGer	Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish
abstract_unstemmed	Summary: A standard approach in the identification of transcriptional enhancers is the use of transgenic animals carrying DNA elements joined to reporter genes inserted randomly in the genome. We examined elements near Tbx5, a gene required for forelimb development in humans and other vertebrates. Previous transgenic studies reported a mammalian Tbx5 forelimb enhancer located in intron 2 containing a putative retinoic acid response element and a zebrafish tbx5a forelimb (pectoral fin) enhancer located downstream that is conserved from fish to mammals. We used CRISPR/Cas9 gene editing to knockout the endogenous elements and unexpectedly found that deletion of the intron 2 and downstream elements, either singly or together in double knockouts, resulted in no effect on forelimb development. Our findings show that reporter transgenes may not identify endogenous enhancers and that in vivo genetic loss-of-function studies are required, such as CRISPR/Cas9, which is similar in effort to production of animals carrying reporter transgenes. : Forelimb development requires Tbx5. Using CRISPR/Cas9 gene editing to create homozygous deletions, Cunningham et al. show that two Tbx5 forelimb enhancers identified with reporter transgenes are not required for Tbx5 activation or forelimb development. These observations demonstrate that knockout studies are required to identify endogenous enhancers necessary for biological processes. Keywords: enhancer, limb development, Tbx5, retinoic acid response element, CRISPR/Cas9 gene editing, mouse, zebrafish
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title_short	Genomic Knockout of Two Presumed Forelimb Tbx5 Enhancers Reveals They Are Nonessential for Limb Development
url	https://doi.org/10.1016/j.celrep.2018.05.052 https://doaj.org/article/efb2be0a509b43199ea7a43d938ee017 http://www.sciencedirect.com/science/article/pii/S2211124718307988 https://doaj.org/toc/2211-1247
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