Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
Development. 2013 Feb;140(4):843-52. doi: 10.1242/dev.088229. Epub 2013 Jan 16.
Environmental factors can stably perturb the epigenome of exposed individuals and even that of their offspring, but the pleiotropic effects of these factors have posed a challenge for understanding the determinants of mitotic or transgenerational inheritance of the epigenetic perturbation. To tackle this problem, we manipulated the epigenetic states of various target genes using a tetracycline-dependent transcription factor. Remarkably, transient manipulation at appropriate times during embryogenesis led to aberrant epigenetic modifications in the ensuing adults regardless of the modification patterns, target gene sequences or locations, and despite lineage-specific epigenetic programming that could reverse the epigenetic perturbation, thus revealing extraordinary malleability of the fetal epigenome, which has implications for 'metastable epialleles'. However, strong transgenerational inheritance of these perturbations was observed only at transgenes integrated at the Col1a1 locus, where both activating and repressive chromatin modifications were heritable for multiple generations; such a locus is unprecedented. Thus, in our inducible animal models, mitotic inheritance of epigenetic perturbation seems critically dependent on the timing of the perturbation, whereas transgenerational inheritance additionally depends on the location of the perturbation. In contrast, other parameters examined, particularly the chromatin modification pattern and DNA sequence, appear irrelevant.
环境因素可以稳定地扰乱暴露个体的表观基因组，甚至扰乱其后代的表观基因组，但这些因素的多效性效应给理解有丝分裂或跨代遗传的表观遗传干扰的决定因素带来了挑战。为了解决这个问题，我们使用四环素依赖性转录因子来操纵各种靶基因的表观状态。值得注意的是，在胚胎发生过程中适当的时间进行短暂的操作，会导致随后的成年个体出现异常的表观遗传修饰，而不管修饰模式、靶基因序列或位置如何，尽管有特定谱系的表观遗传编程可以逆转表观遗传干扰，但这表明胎儿表观基因组具有非凡的可塑，这对“动态等位基因”有影响。然而，只有在 Col1a1 基因座整合的转基因中观察到这些干扰的强烈跨代遗传，在该基因座中，激活和抑制性染色质修饰均可遗传多代；这种基因座是前所未有的。因此，在我们的诱导型动物模型中，表观遗传干扰的有丝分裂遗传似乎严重依赖于干扰的时间，而跨代遗传还取决于干扰的位置。相比之下，检查的其他参数，特别是染色质修饰模式和 DNA 序列，似乎并不相关。
