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猪 ZBED6 通过多个靶标调控骨骼肌和内脏器官的生长。

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

机构信息

Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.

National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.

出版信息

PLoS Genet. 2021 Oct 28;17(10):e1009862. doi: 10.1371/journal.pgen.1009862. eCollection 2021 Oct.

DOI:10.1371/journal.pgen.1009862
PMID:34710100
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8577783/
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.

摘要

ZBED6（锌指 BED 结构域蛋白 6）是胎盘哺乳动物所特有的转录因子，其与 IGF2（胰岛素样生长因子 2）基因座的相互作用在调节出生后骨骼肌生长中起着重要作用。在这里，我们通过生成 ZBED6 敲除（ZBED6-/-）的巴马小型猪来生成瘦小型猪，并研究了 ZBED6 在胎盘哺乳动物肌肉和内脏器官生长中的作用机制。与野生型（WT）猪相比，ZBED6-/-猪的瘦肉量、瘦肉率、肌纤维面积更大，内脏器官（心脏和肝脏）更重。ZBED6-/-猪的显著表型变化与 IGF2 mRNA 和蛋白质表达在三种组织（比目鱼肌、背最长肌、心脏）中的显著上调一致。尽管肝脏重量显著增加，但 ZBED6-/-猪的 IGF2 表达水平与 WT 对照组相当。一项机制研究表明，肝脏中高甲基化会破坏 ZBED6 在 IGF2 基因座上的结合，这解释了 ZBED6-/-猪中肝 IGF2 表达不变的原因。这些结果表明，肝脏中存在一种与 ZBED6-IGF2 无关的调节途径。转录组分析和 ChIP-PCR 揭示了除 IGF2 以外的新的 ZBED6 靶基因，包括细胞周期蛋白依赖性激酶抑制剂 1A（CDKN1A）和小富含亮氨酸的蛋白聚糖（TSKU），它们分别调节肌肉和肝脏的生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/3381de44f293/pgen.1009862.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/27f02f344ead/pgen.1009862.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/fd6a57088558/pgen.1009862.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/0bf5260c49da/pgen.1009862.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/517b986e2290/pgen.1009862.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/3381de44f293/pgen.1009862.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/27f02f344ead/pgen.1009862.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/fd6a57088558/pgen.1009862.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/0bf5260c49da/pgen.1009862.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/517b986e2290/pgen.1009862.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce3/8577783/3381de44f293/pgen.1009862.g005.jpg

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