Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.
Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.
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DOI：
10.1186/gb-2010-11-11-r111
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发表时间：
2010
期刊：
影响因子：
12.3
通讯作者：
Whitelaw E
中科院分区：
文献类型：
--
作者：
Whitelaw NC;Chong S;Morgan DK;Nestor C;Bruxner TJ;Ashe A;Lambley E;Meehan R;Whitelaw E
在受控环境中饲养的近交个体在许多复杂性状上显示出相当大的差异，但这种无形变异的根本原因一直是个谜。在这里，我们表明，表观遗传基因沉默的两个修饰符在这个过程中发挥了关键作用。在DNA甲基转移酶3a（Dnmt3a）或三联体基序蛋白28（Trim28）的无效突变杂合子的近交系小鼠表现出更大的体重变异系数比野生型同窝出生。Trim28突变体还发展代谢综合征和具有不完全代谢的异常行为。全基因组基因表达分析发现，与野生型小鼠相比，Trim28杂合子突变体中有284个显著失调的基因，其中Mas1编码与脂质代谢有关的G蛋白偶联受体，显示出最大的平均表达变化（突变体中高出7.8倍）。该基因在突变个体之间也表现出高度可变的表达。这些研究提供了一个在整个生物体的发育噪音的分子解释，并表明，忠实的转录表观遗传控制是中央抑制有害水平的表型变异。这些发现对于理解人类散发性和复杂疾病的机制具有广泛的意义。
Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. 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 wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals. 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.
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影响因子：
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作者：
Ashe, Alyson;Morgan, Daniel K.;Whitelaw, Nadia C.;Bruxner, Timothy J.;Vickaryous, Nicola K.;Cox, Liza L.;Butterfield, Natalie C.;Wicking, Carol;Blewitt, Marnie E.;Wilkins, Sarah J.;Anderson, Gregory J.;Cox, Timothy C.;Whitelaw, Emma
通讯作者：
Whitelaw, Emma