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

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 b...

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Autores principales:	Dandan Wang, Dengke Pan, Baocai Xie, Shengnan Wang, Xiangyang Xing, Xuexue Liu, Yuehui Ma, Leif Andersson, Jiangwei Wu, Lin Jiang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/ded7deb385c64535b39bd2ae3d86faf6
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spelling	oai:doaj.org-article:ded7deb385c64535b39bd2ae3d86faf62021-11-18T06:15:01ZPorcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets1553-73901553-7404https://doaj.org/article/ded7deb385c64535b39bd2ae3d86faf62021-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577783/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404ZBED6 (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 summary The 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.Dandan WangDengke PanBaocai XieShengnan WangXiangyang XingXuexue LiuYuehui MaLeif AnderssonJiangwei WuLin JiangPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Dandan Wang Dengke Pan Baocai Xie Shengnan Wang Xiangyang Xing Xuexue Liu Yuehui Ma Leif Andersson Jiangwei Wu Lin Jiang Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
description	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 summary The 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.
format	article
author	Dandan Wang Dengke Pan Baocai Xie Shengnan Wang Xiangyang Xing Xuexue Liu Yuehui Ma Leif Andersson Jiangwei Wu Lin Jiang
author_facet	Dandan Wang Dengke Pan Baocai Xie Shengnan Wang Xiangyang Xing Xuexue Liu Yuehui Ma Leif Andersson Jiangwei Wu Lin Jiang
author_sort	Dandan Wang
title	Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
title_short	Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
title_full	Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
title_fullStr	Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
title_full_unstemmed	Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
title_sort	porcine zbed6 regulates growth of skeletal muscle and internal organs via multiple targets
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/ded7deb385c64535b39bd2ae3d86faf6
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Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets

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