ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth

Markljung, Ellen; Jiang, Lin; Jaffe, Jacob D.; Mikkelsen, Tarjei S.; Wallerman, Ola; Larhammar, Martin; Zhang, Xiaolan; Wang, Lili; Saenz-Vash, Veronica; Gnirke, Andreas; Lindroth, Anders M.; Barrès, Romain; Yan, Jie; Strömberg, Sara; De, Sachinandan; Pontén, Fredrik; Lander, Eric S.; Carr, Steven A.; Zierath, Juleen R.; Kullander, Klas; Wadelius, Claes; Lindblad‐Toh, Kerstin; Andersson, Gerhard; Hjälm, Göran; Andersson, Leif

doi:10.1371/journal.pbio.1000256

Cited by 153 publications

(220 citation statements)

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“…Z inc finger BED domain-containing protein 6 (ZBED6) is a recently discovered transcription factor restricted to and highly conserved among placental mammals (1). The intron-less ZBED6 has evolved from a domesticated DNA transposon and is located in one of the first introns of another gene, zinc finger CCCH-type containing 11A (ZC3H11A), with which it has no sequence homology.…”

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“…ZBED6 belongs to the CCCH zinc-finger BEAT and DREF (BED) domain-containing family and contains two DNA-binding BED domains and one hobo-Ac-Tam3 (hATC) dimerization domain. ZBED6 has a broad tissue distribution in mammals (1). In muscle tissue of pigs, it has been observed that ZBED6 negatively regulates insulin-like growth factor-2 (IGF2) transcription (1).…”

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“…ZBED6 has a broad tissue distribution in mammals (1). In muscle tissue of pigs, it has been observed that ZBED6 negatively regulates insulin-like growth factor-2 (IGF2) transcription (1). A G-to-A transition in intron 3 of IGF2 abrogates the binding site for ZBED6 and leads to a threefold upregulation of IGF2 mRNA expression in skeletal muscle.…”

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“…Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified >2,000 ZBED6 binding sites in the genome. Genes associated with ZBED6 binding sites show a highly significant enrichment for certain Gene Ontology (GO) classifications, including development and transcriptional regulation (1).…”

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“…For example, genes coding for transcription factors crucial to the pancreatic beta cell-such as Neurog3, Nkx6.1, NeuroD2, and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA)-were found to be putative binding targets for ZBED6 in myoblast cells (1). ZBED6-mediated control of IGF2 may be relevant to beta cells because it has been observed that aberrant IGF2 production in embryonic pancreas preceded the subsequent beta cell mass anomaly that develops in diabetic Goto-Kakizaki rats (3).…”

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Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Wang

Jiang

Wallerman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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We have investigated whether the recently discovered transcription factor, zinc finger BED domain-containing protein 6 (ZBED6), is expressed in insulin-producing cells and, if so, to what extent it affects beta cell function. ZBED6 was translated from a ZC3H11A transcript in which the ZBED6-containing intron was retained. ZBED6 was present in mouse βTC-6 cells and human islets as a double nuclear band at 115/120 kDa and as a single cytoplasmic band at 95-100 kDa, which lacked N-terminal nuclear localization signals. We propose that ZBED6 supports proliferation and survival of beta cells, possibly at the expense of specialized beta cell function-i.e., insulin production-because (i) the nuclear ZBED6 were the predominant forms in rapidly proliferating βTC-6 cells, but not in human islet cells; (ii) down-regulation of ZBED6 in βTC-6 cells resulted in altered morphology, decreased proliferation, a partial S/G2 cell-cycle arrest, increased expression of beta cell-specific genes, and higher rates of apoptosis; (iii) silencing of ZBED6 in the human PANC-1 duct cell line reduced proliferation rates; and (iv) ZBED6 binding was preferentially to genes that control transcription, macromolecule biosynthesis, and apoptosis. Furthermore, it is possible that beta cells, by switching from full length to a truncated form of ZBED6, can decide the subcellular localization of ZBED6, thereby achieving differential ZBED6-mediated transcriptional regulation.Z inc finger BED domain-containing protein 6 (ZBED6) is a recently discovered transcription factor restricted to and highly conserved among placental mammals (1). The intron-less ZBED6 has evolved from a domesticated DNA transposon and is located in one of the first introns of another gene, zinc finger CCCH-type containing 11A (ZC3H11A), with which it has no sequence homology. ZBED6 belongs to the CCCH zinc-finger BEAT and DREF (BED) domain-containing family and contains two DNA-binding BED domains and one hobo-Ac-Tam3 (hATC) dimerization domain. ZBED6 has a broad tissue distribution in mammals (1). In muscle tissue of pigs, it has been observed that ZBED6 negatively regulates insulin-like growth factor-2 (IGF2) transcription (1). A G-to-A transition in intron 3 of IGF2 abrogates the binding site for ZBED6 and leads to a threefold upregulation of IGF2 mRNA expression in skeletal muscle. Mutant pigs lacking the ZBED6 binding site display increased muscle mass, bigger hearts, and less fat deposition (2). Silencing of ZBED6 in mouse C2C12 myoblast cells was associated with elevated IGF2 expression, increased cell proliferation, and a faster wound-healing process. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified >2,000 ZBED6 binding sites in the genome. Genes associated with ZBED6 binding sites show a highly significant enrichment for certain Gene Ontology (GO) classifications, including development and transcriptional regulation (1).It is possible that ZBED6 controls not only IGF2 expression in muscle, but also the function of insulin-producing beta cells. ...

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Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Wang

Jiang

Wallerman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evolutionary History and Impact of Human DNA Transposons

Feschotte

McCormick

2013

Encyclopedia of Life Sciences

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Deoxyribonucleic acid (DNA) transposons are mobile elements that move via a DNA intermediate. The (haploid) human genome harbours more than 300 000 DNA transposon copies, accounting for approximately 3% of the total genomic DNA. Nearly one‐third of these elements are specific to the primate lineage, but there is no evidence for transposition activity within the past 40 million years. However, there is growing evidence that DNA transposons have contributed in shaping the current genome architecture of humans and have been a recurrent source of new regulatory and coding DNA throughout mammalian evolution. Notably, more than 50 human genes are currently known to descend from transposase sequences recycled to perform diverse cellular functions. Key Concepts: DNA (or class 2) transposons represent a minority of the mobile genetic elements populating mammalian genomes, but still account for more DNA in our genome than all protein‐coding sequences. DNA transposition was once very active in mammals and has generated approximately 100 000 primate‐specific insertions in our genome. DNA transposon germline activity suddenly ceased ∼40 million years ago in the human lineage, but has persisted in other mammalian lineages – most prominently and recently in vesper bats. Despite the lack of current transposition activity, DNA transposons may still be promoting genomic rearrangements, including recurrent ectopic recombination events associated with pathologies. Like many other mobile elements in the human genome, some DNA transposons have been incorporated into the regulatory apparatus of the genome through the donation of enhancers and regulatory elements modulating adjacent gene expression. Transposases have been a source of coding sequences for the assembly of several new genes during vertebrate evolution, including at least 50 genes in the human genome. The function of most human transposase‐derived genes remains unknown or poorly understood, but some have emerged as key regulators for a variety of cellular processes.

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Loss of ZBED6 Protects Against Sepsis‐Induced Muscle Atrophy by Upregulating DOCK3‐Mediated RAC1/PI3K/AKT Signaling Pathway in Pigs

Liu

Pan

et al. 2023

Advanced Science

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Sepsis‐induced muscle atrophy often increases morbidity and mortality in intensive care unit (ICU) patients, yet neither therapeutic target nor optimal animal model is available for this disease. Here, by modifying the surgical strategy of cecal ligation and puncture (CLP), a novel sepsis pig model is created that for the first time recapitulates the whole course of sepsis in humans. With this model and sepsis patients, increased levels of the transcription factor zinc finger BED‐type containing 6 (ZBED6) in skeletal muscle are shown. Protection against sepsis‐induced muscle wasting in ZBED6‐deficient pigs is further demonstrated. Mechanistically, integrated analysis of RNA‐seq and ChIP‐seq reveals dedicator of cytokinesis 3 (DOCK3) as the direct target of ZBED6. In septic ZBED6‐deficient pigs, DOCK3 expression is increased in skeletal muscle and myocytes, activating the RAC1/PI3K/AKT pathway and protecting against sepsis‐induced muscle wasting. Conversely, opposite gene expression patterns and exacerbated muscle wasting are observed in septic ZBED6‐overexpressing myotubes. Notably, sepsis patients show increased ZBED6 expression along with reduced DOCK3 and downregulated RAC1/PI3K/AKT pathway. These findings suggest that ZBED6 is a potential therapeutic target for sepsis‐induced muscle atrophy, and the established sepsis pig model is a valuable tool for understanding sepsis pathogenesis and developing its therapeutics.

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ZBED6, a Novel Transcription Factor Derived from a Domesticated DNA Transposon Regulates IGF2 Expression and Muscle Growth

Abstract: This study identifies a previously uncharacterized protein, encoded by a domesticated DNA transposon, called ZBED6 that regulates the expression of the insulin-like growth factor 2 (IGF2) gene, and possibly numerous others, in all placental mammals including human.

Cited by 153 publications

References 26 publications

Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Transcription factor ZBED6 affects gene expression, proliferation, and cell death in pancreatic beta cells

Evolutionary History and Impact of Human DNA Transposons

Loss of ZBED6 Protects Against Sepsis‐Induced Muscle Atrophy by Upregulating DOCK3‐Mediated RAC1/PI3K/AKT Signaling Pathway in Pigs

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