Department of Biochemistry, University of Oxford, Oxford, UK.
Present Address: Department of Physiology, National University of Singapore, Singapore, Singapore.
BMC Biol. 2021 Mar 25;19(1):59. doi: 10.1186/s12915-021-00984-8.
Evidence of global heterochromatin decay and aberrant gene expression in models of physiological and premature ageing have long supported the "heterochromatin loss theory of ageing", which proposes that ageing is aetiologically linked to, and accompanied by, a progressive, generalised loss of repressive epigenetic signatures. However, the remarkable plasticity of chromatin conformation suggests that the re-establishment of such marks could potentially revert the transcriptomic architecture of animal cells to a "younger" state, promoting longevity and healthspan. To expand our understanding of the ageing process and its connection to chromatin biology, we screened an RNAi library of chromatin-associated factors for increased longevity phenotypes.
We identified the lysine demethylases jmjd-3.2 and utx-1, as well as the lysine methyltransferase mes-2 as regulators of both lifespan and healthspan in C. elegans. Strikingly, we found that both overexpression and loss of function of jmjd-3.2 and utx-1 are all associated with enhanced longevity. Furthermore, we showed that the catalytic activity of UTX-1, but not JMJD-3.2, is critical for lifespan extension in the context of overexpression. In attempting to reconcile the improved longevity associated with both loss and gain of function of utx-1, we investigated the alternative lifespan pathways and tissue specificity of longevity outcomes. We demonstrated that lifespan extension caused by loss of utx-1 function is daf-16 dependent, while overexpression effects are partially independent of daf-16. In addition, lifespan extension was observed when utx-1 was knocked down or overexpressed in neurons and intestine, whereas in the epidermis, only knockdown of utx-1 conferred improved longevity.
We show that the regulation of longevity by chromatin modifiers can be the result of the interaction between distinct factors, such as the level and tissue of expression. Overall, we suggest that the heterochromatin loss model of ageing may be too simplistic an explanation of organismal ageing when molecular and tissue-specific effects are taken into account.
生理和早衰模型中广泛的异染色质衰减和异常基因表达的证据长期以来一直支持“异染色质丢失衰老理论”，该理论提出衰老与逐渐发生的、普遍的抑制性表观遗传特征的丧失有关。然而，染色质构象的惊人可塑性表明，这些标记的重新建立有可能使动物细胞的转录组结构恢复到“年轻”状态，从而促进长寿和健康寿命。为了扩大我们对衰老过程及其与染色质生物学联系的理解，我们筛选了一个与染色质相关因子的 RNAi 文库，以寻找延长寿命的表型。
我们鉴定出赖氨酸去甲基酶 jmjd-3.2 和 utx-1 以及赖氨酸甲基转移酶 mes-2 是秀丽隐杆线虫寿命和健康寿命的调节剂。令人惊讶的是，我们发现 jmjd-3.2 和 utx-1 的过表达和功能丧失都与寿命延长有关。此外，我们表明，在过表达的情况下，UTX-1 的催化活性但不是 JMJD-3.2 的催化活性对延长寿命至关重要。在试图协调 utx-1 功能丧失和获得功能与改善寿命之间的关系时，我们研究了替代的寿命途径和寿命结果的组织特异性。我们证明，utx-1 功能丧失引起的寿命延长依赖于 daf-16，而过表达的影响部分独立于 daf-16。此外，当 utx-1 在神经元和肠道中敲低或过表达时，观察到寿命延长，而在表皮中，只有 utx-1 的敲低才能改善寿命。
我们表明，染色质修饰物对寿命的调节可能是由于不同因素之间的相互作用，例如表达水平和组织。总的来说，当考虑到分子和组织特异性效应时，我们认为异染色质丢失衰老模型可能过于简单地解释了生物体的衰老。
