Open AccessPorcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
Author(s) -
Dandan Wang,
Dengke Pan,
Baocai Xie,
Shengnan Wang,
Xiangyang Xing,
Xuexue Liu,
Yuehui Ma,
Leif Andersson,
Jiangwei Wu,
Lin Jiang
Publication year - 2021
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009862
Subject(s) - biology , skeletal muscle , endocrinology , medicine , growth factor , downregulation and upregulation , transcription factor , microbiology and biotechnology , gene , genetics , receptor
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.