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Research article - Peer-reviewed, 2021

Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets

Wang, Dandan; Pan, Dengke; Xie, Baocai; Wang, Shengnan; Xing, Xiangyang; Liu, Xuexue; Ma, Yuehui; Andersson, Leif; Wu, Jiangwei; Jiang, Lin

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.

Author summaryThe lean meat rate is an important economic trait for the swine industry and it is determined by muscle growth and development. A single base change in intron 3 of the insulin-like growth factor 2 (IGF2) gene increases meat production in pigs by disrupting a binding site for zinc finger BED domain containing protein 6 (ZBED6). Chinese indigenous pig breeds carrying the homozygous IGF2 wild-type allele produce low lean meat. We thus generate a lean pig model in Chinese Bama pig by knocking out ZBED6. In this model, we demonstrate that ZBED6 KO increases muscle and internal organ growth through ZBED6-IGF2 axis and other target genes. These results not only open new strategies for lean meat breeding in Chinese indigenous pigs, but also provide new insights to the global function of ZBED6 in organ growth and development.

Published in

PLOS GENETICS
2021, volume: 17, number: 10, article number: e1009862
Publisher: PUBLIC LIBRARY SCIENCE

Authors' information

Wang, Dandan
Chinese Academy of Agricultural Sciences
Pan, Dengke
Chinese Academy of Agricultural Sciences
Pan, Dengke
Sichuan Provincial People's Hospital
Xie, Baocai
Northwest AandF University - China
Wang, Shengnan
Chinese Academy of Agricultural Sciences
Xing, Xiangyang
Chengdu Clonorgan Biotechnol Co LTD
Liu, Xuexue
Chinese Academy of Agricultural Sciences
Ma, Yuehui
Chinese Academy of Agricultural Sciences
Andersson, Leif
Uppsala University
Andersson, Leif
Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics
Andersson, Leif
Texas A&M University
Wu, Jiangwei
Northwest AandF University - China
Jiang, Lin
Chinese Academy of Agricultural Sciences

UKÄ Subject classification

Animal and Dairy Science

Publication Identifiers

DOI: https://doi.org/10.1371/journal.pgen.1009862

URI (permanent link to this page)

https://res.slu.se/id/publ/114486