ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth

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 Barres; 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

doi:10.1371/journal.pbio.1000256

ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth

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 Barres, Jie Yan, Sara Strömberg, Sachinandan De, Fredrik Pontén, Eric S Lander, Steven A Carr, Juleen R Zierath, Klas KullanderClaes Wadelius, Kerstin Lindblad-Toh, Göran Andersson, Göran Hjälm, Leif Andersson

106 Citations (Scopus)

Abstract

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.

Original language	English
Journal	P L o S Biology (Online)
Volume	7
Issue number	12
Pages (from-to)	e1000256
ISSN	1545-7885
DOIs	https://doi.org/10.1371/journal.pbio.1000256
Publication status	Published - Dec 2009

Keywords

Animals
Carrier Proteins
Cell Line
Cell Nucleolus
Cell Proliferation
Chromatin Immunoprecipitation
DNA Transposable Elements
Gene Expression Regulation, Developmental
Genetic Diseases, Inborn
Humans
Insulin-Like Growth Factor II
Mass Spectrometry
Mice
Muscle Development
Quantitative Trait Loci
RNA Interference
RNA, Small Interfering
Repressor Proteins
Swine
Wound Healing

Access to Document

10.1371/journal.pbio.1000256

Cite this

Markljung, E., Jiang, L., Jaffe, J. D., Mikkelsen, T. S., Wallerman, O., Larhammar, M., Zhang, X., Wang, L., Saenz-Vash, V., Gnirke, A., Lindroth, A. M., Barres, R., Yan, J., Strömberg, S., De, S., Pontén, F., Lander, E. S., Carr, S. A., Zierath, J. R., ... Andersson, L. (2009). ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth. P L o S Biology (Online), 7(12), e1000256. https://doi.org/10.1371/journal.pbio.1000256

Markljung, E, Jiang, L, Jaffe, JD, Mikkelsen, TS, Wallerman, O, Larhammar, M, Zhang, X, Wang, L, Saenz-Vash, V, Gnirke, A, Lindroth, AM, Barres, R, Yan, J, Strömberg, S, De, S, Pontén, F, Lander, ES, Carr, SA, Zierath, JR, Kullander, K, Wadelius, C, Lindblad-Toh, K, Andersson, G, Hjälm, G & Andersson, L 2009, 'ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth', P L o S Biology (Online), vol. 7, no. 12, pp. e1000256. https://doi.org/10.1371/journal.pbio.1000256

@article{363f5f5b9ca84eb08d10c1a86afb7674,

title = "ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth",

abstract = "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.",

keywords = "Animals, Carrier Proteins, Cell Line, Cell Nucleolus, Cell Proliferation, Chromatin Immunoprecipitation, DNA Transposable Elements, Gene Expression Regulation, Developmental, Genetic Diseases, Inborn, Humans, Insulin-Like Growth Factor II, Mass Spectrometry, Mice, Muscle Development, Quantitative Trait Loci, RNA Interference, RNA, Small Interfering, Repressor Proteins, Swine, Wound Healing",

author = "Ellen Markljung and Lin Jiang and Jaffe, {Jacob D} and Mikkelsen, {Tarjei S} and Ola Wallerman and Martin Larhammar and Xiaolan Zhang and Li Wang and Veronica Saenz-Vash and Andreas Gnirke and Lindroth, {Anders M} and Romain Barres and Jie Yan and Sara Str{\"o}mberg and Sachinandan De and Fredrik Pont{\'e}n and Lander, {Eric S} and Carr, {Steven A} and Zierath, {Juleen R} and Klas Kullander and Claes Wadelius and Kerstin Lindblad-Toh and G{\"o}ran Andersson and G{\"o}ran Hj{\"a}lm and Leif Andersson",

year = "2009",

month = dec,

doi = "10.1371/journal.pbio.1000256",

language = "English",

volume = "7",

pages = "e1000256",

journal = "PLoS Biology",

issn = "1544-9173",

publisher = "public library of science",

number = "12",

}

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 - 1544-9173

VL - 7

SP - e1000256

JO - PLoS Biology

JF - PLoS Biology

IS - 12

ER -

ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth

Abstract

Keywords

Access to Document

Fingerprint

Cite this