TY - JOUR
T1 - ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth
AU - Markljung, Ellen
AU - Jiang, Lin
AU - Jaffe, Jacob D
AU - Mikkelsen, Tarjei S
AU - Wallerman, Ola
AU - Larhammar, Martin
AU - Zhang, Xiaolan
AU - Wang, Li
AU - Saenz-Vash, Veronica
AU - Gnirke, Andreas
AU - Lindroth, Anders M
AU - Barres, Romain
AU - Yan, Jie
AU - Strömberg, Sara
AU - De, Sachinandan
AU - Pontén, Fredrik
AU - Lander, Eric S
AU - Carr, Steven A
AU - Zierath, Juleen R
AU - Kullander, Klas
AU - Wadelius, Claes
AU - Lindblad-Toh, Kerstin
AU - Andersson, Göran
AU - Hjälm, Göran
AU - Andersson, Leif
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
KW - Animals
KW - Carrier Proteins
KW - Cell Line
KW - Cell Nucleolus
KW - Cell Proliferation
KW - Chromatin Immunoprecipitation
KW - DNA Transposable Elements
KW - Gene Expression Regulation, Developmental
KW - Genetic Diseases, Inborn
KW - Humans
KW - Insulin-Like Growth Factor II
KW - Mass Spectrometry
KW - Mice
KW - Muscle Development
KW - Quantitative Trait Loci
KW - RNA Interference
KW - RNA, Small Interfering
KW - Repressor Proteins
KW - Swine
KW - Wound Healing
U2 - 10.1371/journal.pbio.1000256
DO - 10.1371/journal.pbio.1000256
M3 - Journal article
C2 - 20016685
SN - 1545-7885
VL - 7
SP - e1000256
JO - P L o S Biology (Online)
JF - P L o S Biology (Online)
IS - 12
ER -