A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.
A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.
复制标题
反转录转座子上自发的遗传诱导表观等位基因塑造宿主基因组功能。
DOI：
10.7554/elife.65233
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发表时间：
2021-03-23
期刊：
影响因子：
7.7
通讯作者：
Ferguson-Smith AC
中科院分区：
文献类型：
--
作者：
Bertozzi TM;Takahashi N;Hanin G;Kazachenka A;Ferguson-Smith AC
脑池内A颗粒（IAP）是内源性逆转录病毒（ERV），负责小鼠中的大多数插入突变。全长IAP含有侧翼为长末端重复序列（LTR）的基因。在这里，我们确定了一个单独的LTR IAP变异（Iap5 - 1solo）最近形成的近交系C57 BL/6J小鼠品系。与C57BL/6J在该基因座处的全长IAP（Iap5 - 1full）相反，Iap5 - 1solo缺乏DNA甲基化和H3K9三甲基化。两个等位基因之间不同的DNA甲基化水平是在植入前发育过程中建立的，可能是由于Iap5 - 1solo变体处KRAB锌指蛋白结合的丧失。Iap5 - 1solo甲基化增加，并成为更多变的混合遗传背景，但母亲的膳食甲基补充剂没有反应。两种变体的差异表观遗传修饰与相邻基因表达的代谢差异和组织特异性变化相关。我们的Iap5 - 1作为一个遗传诱导的表观等位基因的功能后果的特点建立了一个新的模型来研究转座因子的阻遏和主机元件的共同进化。我们的基因组为生命提供了一套完整的遗传指令。它首先指导胚胎的生长和发育，随后支持成年身体的所有细胞的日常活动。然而，哺乳动物基因组中大约10%的DNA是由过去的逆转录病毒感染序列组成的，在我们的遗传密码中留下了一张名片。虽然这些逆转录病毒DNA片段不能再产生新的感染性病毒，但其中一些保留了复制自身并跳跃到基因组新部分的能力。如果它们进入并破坏了一段重要的遗传密码，这可能是有问题的。为了防止这种情况，我们的身体已经进化出了通过向逆转录病毒序列添加甲基基团和修改它们包裹的蛋白质来化学捆绑逆转录病毒序列的能力。然而，这些内源性逆转录病毒中的一些可以避开这种所谓的表观遗传修饰，并因此破坏基因组功能。通过研究一群广泛使用的近交系实验室小鼠，Bertozzi等人发现了一种逆转录病毒因子，它可以逃避这些表观遗传学的限制。他们发现，一些小鼠携带全长逆转录病毒序列，而另一些小鼠则具有相同元件的缩短版本。较短的序列缺乏在较长版本上发现的抑制性表观遗传标记，这影响了附近基因的表达。此外，通过将短型小鼠与远亲小鼠品系交配，抑制标记可以部分恢复。Bertozzi等人强调了使用小鼠模型进行研究的一个重要问题。近亲繁殖的实验室小鼠品系被假定具有固定的遗传密码，这使得科学家能够得出结论，在他们的实验中观察到的任何差异都不是背景遗传变异的产物。然而，这项研究强调，这一假设并不能得到保证，隐藏的遗传多样性可能存在于表面上遗传相同的小鼠中，对实验结果具有重要意义。此外，Bertozzi等人为研究人员提供了一种新的小鼠模型，用于研究逆转录病毒序列的进化和调控以及这些过程对细胞功能的影响。
Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution. Our genome provides a complete set of genetic instructions for life. It begins by directing the growth and development of the embryo, and subsequently supports all the cells of the adult body in their daily routines. Yet approximately 10% of the DNA in mammalian genomes is made up of sequences originating from past retroviral infections, leaving a calling card in our genetic code. While these segments of retroviral DNA can no longer produce new infectious viruses, some of them retain the ability to copy themselves and jump into new parts of the genome. This can be problematic if they jump into and disrupt an important piece of genetic code. To protect against this, our bodies have evolved the ability to chemically strap down retroviral sequences by adding methyl groups to them and by modifying the proteins they are wrapped around. However, some of these endogenous retroviruses can dodge such so-called epigenetic modifications and disrupt genome function as a result. Studying a population of widely used inbred laboratory mice, Bertozzi et al. have identified a retroviral element that evades these epigenetic restraints. They discovered that some mice carry a full-length retroviral sequence while others have a shortened version of the same element. The shorter sequence lacked the repressive epigenetic marks found on the longer version, and this affected the expression of nearby genes. Moreover, the repressive marks could be partially restored by breeding the short-version mice with a distantly related mouse strain. Bertozzi et al. highlight an important issue for research using mouse models. Inbred laboratory mouse strains are assumed to have a fixed genetic code which allows scientists to conclude that any observed differences in their experiments are not a product of background genetic variation. However, this study emphasizes that this assumption is not guaranteed, and that hidden genetic diversity may be present in ostensibly genetically identical mice, with important implications for experimental outcomes. In addition, Bertozzi et al. provide a new mouse model for researchers to study the evolution and regulation of retroviral sequences and the impact of these processes on cell function.