Morandini Francesco, Lu Jinlong Y, Rechsteiner Cheyenne, Shadyab Aladdin H, Casanova Ramon, Snively Beverly M, Seluanov Andrei, Gorbunova Vera
Department of Biology, University of Rochester, Rochester, NY, USA.
Herbert Wertheim School of Public Health and Human Longevity Science and Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Nat Aging. 2025 Feb;5(2):193-204. doi: 10.1038/s43587-024-00757-2. Epub 2024 Nov 27.
Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer.
转座元件（TEs）是在基因组中自私地扩增的DNA序列，可能会导致严重的细胞损伤。虽然TEs通常处于沉默状态，但研究表明它们在衰老过程中会被激活。DNA 5-甲基胞嘧啶（5mC）是使TEs沉默的主要表观遗传修饰之一，已被用于训练高度准确的年龄预测模型。然而，对这类预测模型的一个常见批评是它们缺乏可解释性。在本研究中，我们利用已发表的甲基化阵列数据，研究了人类血液衰老过程中转座元件5mC甲基化的变化。我们发现，进化上年轻的长散在核元件1（L1s），即人类中唯一已知的能够自主转座的转座元件，其5mC甲基化的丢失速度最快，这表明存在一种去抑制的活跃机制。同样的年轻L1s在染色质可及性方面也表现出优先增加，但在表达方面没有增加。长末端重复逆转座子THE1A和THE1C也显示出非常快速的5mC丢失。然后我们表明，可以根据单个转座元件拷贝的5mC甲基化和全基因组转座元件家族的平均甲基化来训练准确的年龄预测模型。最后，我们表明，虽然老的L1s在整个生命周期中逐渐失去5mC，但年轻L1s的去甲基化只发生在生命后期，并且与癌症有关。
