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The molecular basis for stability of heterochromatin-mediated silencing in mammals

机译：异染色质介导的沉默在哺乳动物中稳定的分子基础

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The archetypal epigenetic phenomenon of position effect variegation (PEV) in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac) and lysine 4 di or tri methylation (H3K4me2/3) are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.
机译：果蝇的位置效应变异（PEV）的原型表观遗传现象是当基因异常接近异染色质时发生的，导致受影响的基因在一定比例的正常表达该基因的细胞中随机沉默。 PEV有助于阐明表观遗传机制。使用针对PEV的体内哺乳动物模型，我们已经广泛研究了异染色质介导的基因沉默的分子基础。在这里，我们通过研究相同的离体细胞来区分“表观遗传效应”与其他细胞差异，除了在一部分细胞中沉默的杂色基因的表达之外。通过根据转基因表达分离细胞，我们在此处显示沉默似乎与组蛋白H3赖氨酸9三甲基化（H3K9me3），DNA甲基化以及沉默基因在富含这些修饰的特定核区室中的定位有关。相比之下，组蛋白H3乙酰化（H3Ac）和赖氨酸4 di或三甲基化（H3K4me2 / 3）是与表达相关的主要修饰，我们在正常染色区室中看到该基因。有趣的是，DNA甲基化和不可及性，而不是H3K9me3，与细胞激活引起的抑制抑制作用密切相关。这些结果对于理解参与体内基因沉默和激活的建立和维持的特定因素的贡献具有重要意义。

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