Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
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DOI：
10.1016/j.cell.2015.12.025
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发表时间：
2016-01-28
期刊：
影响因子：
64.5
通讯作者：
Pospisilik JA
中科院分区：
文献类型：
--
作者：
Dalgaard K;Landgraf K;Heyne S;Lempradl A;Longinotto J;Gossens K;Ruf M;Orthofer M;Strogantsev R;Selvaraj M;Lu TT;Casas E;Teperino R;Surani MA;Zvetkova I;Rimmington D;Tung YC;Lam B;Larder R;Yeo GS;O'Rahilly S;Vavouri T;Whitelaw E;Penninger JM;Jenuwein T;Cheung CL;Ferguson-Smith AC;Coll AP;Körner A;Pospisilik JA
超过五亿人肥胖，尽管基因研究取得了进展，但肥胖的遗传性仍然是个谜。在这里，我们确定了一个Trim 28依赖的网络能够触发肥胖的非孟德尔，“开/关”的方式。Trim 28 +/D9突变小鼠表现出双峰体重分布，同基因动物随机出现正常或肥胖，很少有中间体。我们发现，肥胖的“开”状态的特征在于减少了包括Nnat、Peg 3、Cdkn 1c和Plagl 1的印迹基因网络的表达，并且这些等位基因的独立靶向概括了随机双稳态疾病表型。儿童的脂肪组织转录组分析表明，人类也聚集成不同的亚群，根据Trim 28表达，转录组组织和肥胖相关的印记基因失调进行分层。这些数据提供了小鼠和人的离散多型性的证据，因此对复杂性状遗传学，进化和医学具有重要意义。Trim 28单倍不足触发随机双稳态肥胖或多型性非经典印记基因失调指定“开”与“关”肥胖状态Peg 3和Nnat扰动触发随机双稳态肥胖人类BMI分布和转录组表明小鼠和人类中的Trim 28相关亚群TRIM 28不足导致多型性，其中瘦型和肥胖型可以通过印记基因网络的失调由相同的基因型引起。
More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, “on/off” manner. Trim28+/D9 mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-“on” state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine. Trim28 haploinsufficiency triggers stochastic bi-stable obesity or polyphenism Non-classical imprinted gene dysregulation specifies “on” versus “off” obese states Peg3 and Nnat perturbation trigger stochastic bi-stable obesity Human BMI distributions and transcriptomes suggest Trim28-associated subpopulations TRIM28 insufficiency in both mouse and human leads to polyphenism, wherein lean and obese phenotypes can arise from the identical genotypes through dysregulation of an imprinted gene network.