Abstract
ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6−/−) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6−/− pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6-/- pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6-/- pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6-/- pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively.
Highlights
Modern commercial pigs have increased skeletal muscle mass and reduced backfat thickness due to the strong selection for lean meat production
The lean meat rate is an important economic trait for the swine industry and it is determined by muscle growth and development
We demonstrate that zinc finger BED domain containing protein 6 (ZBED6) KO increases muscle and internal organ growth through ZBED6-insulin-like growth factor 2 (IGF2) axis and other target genes
Summary
Modern commercial pigs have increased skeletal muscle mass and reduced backfat thickness due to the strong selection for lean meat production. The mutation, located in an evolutionarily conserved CpG island, abrogates a binding site for zinc finger BED domain containing protein 6 (ZBED6) and results in a 3-fold greater postnatal expression of IGF2 mRNA in skeletal muscle [4]. ZBED6 has been shown to regulate IGF2 mRNA expression and insulin production in several human and murine cell lines [6,7,8,9]. Chromatin immunoprecipitation (ChIP) sequencing using murine C2C12 cells demonstrated that ZBED6 may regulate additional 1200 ZBED6 binding sites other than IGF2[4]. The functional role of ZBED6 in pig besides its important role for regulating IGF2 expression is still poorly characterized
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