Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Inbred individuals reared in controlled environments display considerable variance in many complex traits. The underlying cause of this variability has been an enigma, hence the term intangible variation. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28), show greater coefficients of variance in body weight than their wildtype littermates. Inbred mice carrying a mutation in Trim28 develop metabolic syndrome and abnormal behaviour with incomplete penetrance. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans. Liver gene expression in Trim28MommeD9 heterozygotes compared to wildtype littermates.在可控环境中饲养的近交个体，在诸多复杂性状上均表现出显著的表型变异。该类变异的潜在成因始终是一个未解之谜，因此被称为隐匿性变异。本研究证实，两种表观遗传基因沉默（epigenetic gene silencing）调控因子在该过程中发挥关键作用。与野生型同窝仔鼠相比，携带DNA甲基转移酶3a（DNA methyltransferase 3a, Dnmt3a）或三重基序蛋白28（tripartite motif protein 28, Trim28）功能缺失杂合突变的近交小鼠，其体重的变异系数（coefficient of variance）显著更高。携带Trim28突变的近交小鼠会出现代谢综合征（metabolic syndrome）与行为异常，且该表型呈现不完全外显率（incomplete penetrance）。本研究为完整生物体的发育噪声（developmental noise）提供了分子层面的解释，并表明转录的精准表观遗传调控是抑制有害表型变异的核心机制。该研究结果对于解析人类散发性疾病与复杂疾病的潜在发病机制具有广泛的参考价值。本研究还对Trim28^MommeD9杂合子与野生型同窝仔鼠的肝脏基因表达谱进行了对比分析。