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

Wang, Dandan and Pan, Dengke and Xie, Baocai and Wang, Shengnan and Xing, Xiangyang and Liu, Xuexue and Ma, Yuehui and Andersson, Leif and Wu, Jiangwei and Jiang, Lin (2021). Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets. PLOS GENETICS. 17 , e1009862
[Research article]

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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.

Authors/Creators:Wang, Dandan and Pan, Dengke and Xie, Baocai and Wang, Shengnan and Xing, Xiangyang and Liu, Xuexue and Ma, Yuehui and Andersson, Leif and Wu, Jiangwei and Jiang, Lin
Title:Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
Series Name/Journal:PLOS GENETICS
Year of publishing :2021
Volume:17
Article number:e1009862
Number of Pages:18
Publisher:PUBLIC LIBRARY SCIENCE
ISSN:1553-7404
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 4 Agricultural Sciences > 402 Animal and Dairy Science > Animal and Dairy Science.
URN:NBN:urn:nbn:se:slu:epsilon-p-114486
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-114486
Additional ID:
Type of IDID
DOI10.1371/journal.pgen.1009862
Web of Science (WoS)000717907000001
ID Code:26252
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Animal Breeding and Genetics
Deposited By: SLUpub Connector
Deposited On:01 Dec 2021 12:25
Metadata Last Modified:01 Dec 2021 12:31

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