The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals.
The ZBED6-IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals.
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DOI：
10.1073/pnas.1719278115
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发表时间：
2018-02-27
影响因子：
11.1
通讯作者：
Andersson L
中科院分区：
文献类型：
--
作者：
Younis S;Schönke M;Massart J;Hjortebjerg R;Sundström E;Gustafson U;Björnholm M;Krook A;Frystyk J;Zierath JR;Andersson L
胰岛素样生长因子2（IGF 2）是一种重要的生长因子，对哺乳动物的胎儿生长具有关键作用。ZBED 6转录因子是胎盘哺乳动物所特有的，并且是从驯化的DNA转座子进化而来的。这项研究表明，ZBED 6及其与Igf 2基因座的相互作用在调节胎盘哺乳动物骨骼肌和内脏器官（肾脏，肝脏和心脏）的出生后生长中起着重要作用。这种在哺乳动物生物学中的突出作用提供了一个合理的解释，为什么ZBED 6在所有胎盘哺乳动物家族中高度保守，以及为什么包含Igf 2内含子中ZBED 6结合位点的16个碱基对在绝大多数（如果不是全部）胎盘哺乳动物中保守。胰岛素样生长因子2（IGF 2）第三内含子中的单核苷酸取代与家猪肌肉质量增加和皮下脂肪减少相关。这种突变破坏了ZBED 6转录因子的结合，导致猪骨骼肌中IGF 2表达上调三倍。在这里，我们研究了ZBED 6-IGF 2相互作用在胎盘哺乳动物生长中的生物学意义，使用两种小鼠模型，ZBED 6敲除（Zbed 6 −/−）和携带猪IGF 2突变的Igf 2敲入小鼠。这些转基因小鼠表现出明显更高的血清IGF 2浓度，更高的生长速度，增加瘦体重，更大的心脏，肾脏和肝脏;没有观察到白色脂肪组织的显着变化。体重和瘦体重的变化在雌性小鼠中最为明显。表型的变化伴随着一个显着的上调Igf 2在成人组织中的表达。骨骼肌的转录组分析确定了属于细胞外区域类别的基因的差异表达。使用胎儿肌肉的表达分析表明ZBED 6在产前调节Igf 2表达中的次要作用。此外，成人骨骼肌的转录组分析显示，这种升高的Igf 2表达来自P1和P2启动子。结果显示Zbed 6敲除小鼠和Igf 2敲入小鼠中非常相似的表型效应，表明Zbed 6对肌肉和内脏器官生长的影响是通过Igf 2基因中的结合位点介导的。结果解释了为什么ZBED 6结合位点在胎盘哺乳动物中非常保守。
Insulin-like growth factor 2 (IGF2) is an important growth factor with a critical role for fetal growth in mammals. The ZBED6 transcription factor is unique to placental mammals and has evolved from a domesticated DNA transposon. This study shows that ZBED6 and its interaction with the Igf2 locus play a prominent role in regulating postnatal growth of skeletal muscle and internal organs (kidney, liver, and heart) in placental mammals. This prominent role in mammalian biology provides a reasonable explanation why ZBED6 is highly conserved among all families of placental mammals and why 16 base pairs encompassing the ZBED6 binding site in an intron of Igf2 are conserved among the great majority of, if not all, placental mammals. A single nucleotide substitution in the third intron of insulin-like growth factor 2 (IGF2) is associated with increased muscle mass and reduced subcutaneous fat in domestic pigs. This mutation disrupts the binding of the ZBED6 transcription factor and leads to a threefold up-regulation of IGF2 expression in pig skeletal muscle. Here, we investigated the biological significance of ZBED6–IGF2 interaction in the growth of placental mammals using two mouse models, ZBED6 knock-out (Zbed6−/−) and Igf2 knock-in mice that carry the pig IGF2 mutation. These transgenic mice exhibit markedly higher serum IGF2 concentrations, higher growth rate, increased lean mass, and larger heart, kidney, and liver; no significant changes were observed for white adipose tissues. The changes in body and lean mass were most pronounced in female mice. The phenotypic changes were concomitant with a remarkable up-regulation of Igf2 expression in adult tissues. Transcriptome analysis of skeletal muscle identified differential expression of genes belonging to the extracellular region category. Expression analysis using fetal muscles indicated a minor role of ZBED6 in regulating Igf2 expression prenatally. Furthermore, transcriptome analysis of the adult skeletal muscle revealed that this elevated expression of Igf2 was derived from the P1 and P2 promoters. The results revealed very similar phenotypic effects in the Zbed6 knock-out mouse and in the Igf2 knock-in mouse, showing that the effect of ZBED6 on growth of muscle and internal organs is mediated through the binding site in the Igf2 gene. The results explain why this ZBED6 binding site is extremely well conserved among placental mammals.
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影响因子：
46.9
作者：
Trapnell C;Williams BA;Pertea G;Mortazavi A;Kwan G;van Baren MJ;Salzberg SL;Wold BJ;Pachter L
通讯作者：
Pachter L
DOI：
10.1073/pnas.73.12.4379
发表时间：
1976-01-01
影响因子：
11.1
作者：
RINDERKNECHT, E;HUMBEL, RE
通讯作者：
HUMBEL, RE
影响因子：
64.8
作者：
Van Laere, AS;Nguyen, M;Andersson, L
通讯作者：
Andersson, L
影响因子：
9.8
作者：
Markljung E;Jiang L;Jaffe JD;Mikkelsen TS;Wallerman O;Larhammar M;Zhang X;Wang L;Saenz-Vash V;Gnirke A;Lindroth AM;Barrés R;Yan J;Strömberg S;De S;Pontén F;Lander ES;Carr SA;Zierath JR;Kullander K;Wadelius C;Lindblad-Toh K;Andersson G;Hjälm G;Andersson L
通讯作者：
Andersson L
影响因子：
3.5
作者：
Engel, Nora;Thorvaldsen, Joanne L.;Bartolomei, Marisa S.
通讯作者：
Bartolomei, Marisa S.