Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Semin Cell Dev Biol. 2020 Jan;97:93-105. doi: 10.1016/j.semcdb.2019.08.002. Epub 2019 Sep 21.
Many epigenetic differences between individuals are driven by genetic variation. Mammalian metastable epialleles are unusual in that they show variable DNA methylation states between genetically identical individuals. The occurrence of such states across generations has resulted in their consideration by many as strong evidence for epigenetic inheritance in mammals, with the classic A and Axin mouse models - each products of repeat element insertions - being the most widely accepted examples. Equally, there has been interest in exploring their use as epigenetic biosensors given their susceptibility to environmental compromise. Here we review the classic murine metastable epialleles as well as more recently identified candidates, with the aim of providing a more holistic understanding of their biology. We consider the extent to which epigenetic inheritance occurs at metastable epialleles and explore the limited mechanistic insights into the establishment of their variable epigenetic states. We discuss their environmental modulation and their potential relevance in genome regulation. In light of recent whole-genome screens for novel metastable epialleles, we point out the need to reassess their biological relevance in multi-generational studies and we highlight their value as a model to study repeat element silencing as well as the mechanisms and consequences of mammalian epigenetic stochasticity.
许多个体之间的表观遗传差异是由遗传变异驱动的。哺乳动物的不稳定表观等位基因不同寻常，因为它们在遗传上相同的个体之间表现出可变的 DNA 甲基化状态。这些状态在代际间的出现，使得许多人认为它们是哺乳动物中表观遗传遗传的有力证据，经典的 A 和 Axin 小鼠模型——每个都是重复元件插入的产物——是最被广泛接受的例子。同样，由于它们容易受到环境破坏的影响，人们也对探索它们作为表观遗传生物传感器的用途感兴趣。在这里，我们回顾了经典的鼠类不稳定表观等位基因，以及最近确定的候选基因，旨在更全面地了解它们的生物学特性。我们考虑了在不稳定的表观等位基因中发生表观遗传遗传的程度，并探讨了建立其可变表观遗传状态的有限机制见解。我们讨论了它们对环境的调节及其在基因组调节中的潜在相关性。鉴于最近对新型不稳定表观等位基因的全基因组筛查，我们指出需要在多代研究中重新评估它们的生物学相关性，并强调它们作为研究重复元件沉默以及哺乳动物表观遗传随机性的机制和后果的模型的价值。
