ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth.
A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and fin...
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2009
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oai:doaj.org-article:de9e5045bde1421896199b15ecd030972021-11-25T05:34:27ZZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth.1544-91731545-788510.1371/journal.pbio.1000256https://doaj.org/article/de9e5045bde1421896199b15ecd030972009-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20016685/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and find that the protein, named ZBED6, is previously unknown, specific for placental mammals, and derived from an exapted DNA transposon. Silencing of Zbed6 in mouse C2C12 myoblasts affected Igf2 expression, cell proliferation, wound healing, and myotube formation. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified about 2,500 ZBED6 binding sites in the genome, and the deduced consensus motif gave a perfect match with the established binding site in Igf2. Genes associated with ZBED6 binding sites showed a highly significant enrichment for certain Gene Ontology classifications, including development and transcriptional regulation. The phenotypic effects in mutant pigs and ZBED6-silenced C2C12 myoblasts, the extreme sequence conservation, its nucleolar localization, the broad tissue distribution, and the many target genes with essential biological functions suggest that ZBED6 is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth.Ellen MarkljungLin JiangJacob D JaffeTarjei S MikkelsenOla WallermanMartin LarhammarXiaolan ZhangLi WangVeronica Saenz-VashAndreas GnirkeAnders M LindrothRomain BarrésJie YanSara StrömbergSachinandan DeFredrik PonténEric S LanderSteven A CarrJuleen R ZierathKlas KullanderClaes WadeliusKerstin Lindblad-TohGöran AnderssonGöran HjälmLeif AnderssonPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 7, Iss 12, p e1000256 (2009) |
| institution |
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| collection |
DOAJ |
| language |
EN |
| topic |
Biology (General) QH301-705.5 |
| spellingShingle |
Biology (General) QH301-705.5 Ellen Markljung Lin Jiang Jacob D Jaffe Tarjei S Mikkelsen Ola Wallerman Martin Larhammar Xiaolan Zhang Li Wang Veronica Saenz-Vash Andreas Gnirke Anders M Lindroth Romain Barrés Jie Yan Sara Strömberg Sachinandan De Fredrik Pontén Eric S Lander Steven A Carr Juleen R Zierath Klas Kullander Claes Wadelius Kerstin Lindblad-Toh Göran Andersson Göran Hjälm Leif Andersson ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| description |
A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and find that the protein, named ZBED6, is previously unknown, specific for placental mammals, and derived from an exapted DNA transposon. Silencing of Zbed6 in mouse C2C12 myoblasts affected Igf2 expression, cell proliferation, wound healing, and myotube formation. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified about 2,500 ZBED6 binding sites in the genome, and the deduced consensus motif gave a perfect match with the established binding site in Igf2. Genes associated with ZBED6 binding sites showed a highly significant enrichment for certain Gene Ontology classifications, including development and transcriptional regulation. The phenotypic effects in mutant pigs and ZBED6-silenced C2C12 myoblasts, the extreme sequence conservation, its nucleolar localization, the broad tissue distribution, and the many target genes with essential biological functions suggest that ZBED6 is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth. |
| format |
article |
| author |
Ellen Markljung Lin Jiang Jacob D Jaffe Tarjei S Mikkelsen Ola Wallerman Martin Larhammar Xiaolan Zhang Li Wang Veronica Saenz-Vash Andreas Gnirke Anders M Lindroth Romain Barrés Jie Yan Sara Strömberg Sachinandan De Fredrik Pontén Eric S Lander Steven A Carr Juleen R Zierath Klas Kullander Claes Wadelius Kerstin Lindblad-Toh Göran Andersson Göran Hjälm Leif Andersson |
| author_facet |
Ellen Markljung Lin Jiang Jacob D Jaffe Tarjei S Mikkelsen Ola Wallerman Martin Larhammar Xiaolan Zhang Li Wang Veronica Saenz-Vash Andreas Gnirke Anders M Lindroth Romain Barrés Jie Yan Sara Strömberg Sachinandan De Fredrik Pontén Eric S Lander Steven A Carr Juleen R Zierath Klas Kullander Claes Wadelius Kerstin Lindblad-Toh Göran Andersson Göran Hjälm Leif Andersson |
| author_sort |
Ellen Markljung |
| title |
ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| title_short |
ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| title_full |
ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| title_fullStr |
ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| title_full_unstemmed |
ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. |
| title_sort |
zbed6, a novel transcription factor derived from a domesticated dna transposon regulates igf2 expression and muscle growth. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/de9e5045bde1421896199b15ecd03097 |
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