Ectopic expression cool DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype
Ectopic expression cool DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype
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DOI：
10.1016/j.cub.2004.09.079
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发表时间：
2004-10-26
期刊：
影响因子：
9.2
通讯作者：
Charlier, C
中科院分区：
文献类型：
--
作者：
Davis, E;Jensen, CH;Charlier, C
callipyge (CLPG) 表型是绵羊的一种遗传性骨骼肌肥大。它的特点是一种不寻常的遗传模式（“极性过度显性”），其中只有从父亲那里接受了 CLPG 突变 (+(MAT)/CLPG(PAT)) 的杂合个体才会表达该表型 [1]。 +(MAT)/CLPG(PAT) 个体出生时正常，并在大约 1 个月大时出现肌肉肥大。 CLPG 突变被鉴定为位于印记 DLK1 和 GTL2 基因之间高度保守的十二聚体基序中的 A 到 G 转变 [2, 3]。该基序被认为是远程控制元件 (LRCE) 的一部分，因为在出生后骨骼肌中显示 CLPG 突变可增强顺式 DLK1、PEG11、GTL2 和 MEG8 基因的转录水平，而不改变其印记状态 [4]。因此，+(MAT)/CLPG(PAT) 个体具有独特的表达谱，被认为是 callipyge 表型的基础：父系表达的编码 DLK1 的蛋白质（图 1A）和 PEG11 转录物的过度表达，而母系表达的非编码 GTL2 和 MEG8 转录物没有过度表达 [4]。然而，这种独特的表达谱导致 callipyge 肌肉肥大的方式仍不清楚。在此，我们证明，callipyge 表型与 +(MAT)/CLPG(PAT) 羊肥大肌肉中 DLK1 蛋白的异位表达完全相关。我们通过在骨骼肌中表达 DLK1 的转基因小鼠中诱导全身性肌肉肥大来证明这种关联的因果关系。尽管存在 DLK1 mRNA，但 CLPG/ CLPG 动物的骨骼肌中不存在 DLK1 蛋白，这支持由母体等位基因表达的非编码 RNA 介导的反式抑制。
The callipyge (CLPG) phenotype is an inherited skeletal muscle hypertrophy described in sheep. It is characterized by an unusual mode of inheritance ("polar over-dominance") in which only heterozygous individuals having received the CLPG mutation from their father (+(MAT)/CLPG(PAT)) express the phenotype [1]. +(MAT)/CLPG(PAT) individuals are born normal and develop the muscular hypertrophy at approximately 1 month of age. The CLPG mutation was identified as an A to G transition in a highly conserved dodecamer motif located between the imprinted DLK1 and GTL2 genes [2, 3]. This motif is thought to be part of a long-range control element (LRCE) because the CLPG mutation was shown, in postnatal skeletal muscle, to enhance the transcript levels of the DLK1, PEG11, GTL2, and MEG8 genes in cis without altering their imprinting status [4]. As a result, the +(MAT)/CLPG(PAT) individuals have a unique expression profile thought to underlie the callipyge phenotype: an overexpression of the paternally expressed protein encoding DLK1 (Figure 1A) and PEG11 transcripts in the absence of an overexpression of the maternally expressed noncoding GTL2 and MEG8 transcripts [4]. However, the way in which this distinct expression profile causes the callipyge muscular hypertrophy has remained unclear. Herein, we demonstrate that the callipyge phenotype is perfectly correlated with ectopic expression of DLK1 protein in hypertrophied muscle of +(MAT)/CLPG(PAT) sheep. We demonstrate the causality of this association by inducing a generalized muscular hypertrophy in transgenic mice that express DLK1 in skeletal muscle. The absence of DLK1 protein in skeletal muscle of CLPG/ CLPG animals, despite the presence of DLK1 mRNA, supports a trans inhibition mediated by noncoding RNAs expressed from the maternal allele.