Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore.
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
Aging Cell. 2021 May;20(5):e13348. doi: 10.1111/acel.13348. Epub 2021 Mar 31.
NELF-mediated pausing of RNA polymerase II (RNAPII) constitutes a crucial step in transcription regulation. However, it remains unclear how control release of RNAPII pausing can affect the epigenome and regulate important aspects of animal physiology like aging. We found that NELF-A dosage regulates Drosophila healthspan: Halving NELF-A level in the heterozygous mutants or via neuronal-specific RNAi depletion improves their locomotor activity, stress resistance, and lifespan significantly. Conversely, NELF-A overexpression shortens fly lifespan drastically. Mechanistically, lowering NELF-A level facilitates the release of paused RNAPII for productive transcription of the heat-shock protein (Hsp) genes. The elevated HSPs expression in turn attenuates the accumulation of insoluble protein aggregates, reactive oxidative species, DNA damage and systemic inflammation in the brains of aging NELF-A depleted flies as compared to their control siblings. This pro-longevity effect is unique to NELF-A due to its higher expression level and more efficient pausing of RNAPII than other NELF subunits. Importantly, enhanced resistance to oxidative stress in NELF-A heterozygous mutants is highly conserved such that knocking down its level in human SH-SY5Y cells attenuates hydrogen peroxide-induced DNA damage and apoptosis. Depleting NELF-A reconfigures the epigenome through the maintenance of H3K9me2-enriched heterochromatin during aging, leading to the repression of specific retrotransposons like Gypsy-1 in the brains of NELF-A mutants. Taken together, we showed that the dosage of neuronal NELF-A affects multiple aspects of aging in Drosophila by regulating transcription of Hsp genes in the brains, suggesting that targeting transcription elongation might be a viable therapeutic strategy against age-onset diseases like neurodegeneration.
NELF 介导的 RNA 聚合酶 II（RNAPII）暂停是转录调控的关键步骤。然而，控制 RNAPII 暂停的释放如何影响表观基因组以及调节动物生理学的重要方面，如衰老，仍然不清楚。我们发现 NELF-A 剂量调节果蝇的健康寿命：杂合突变体中 NELF-A 水平减半或通过神经元特异性 RNAi 耗竭可显著提高其运动活性、应激抗性和寿命。相反，NELF-A 的过表达会大大缩短果蝇的寿命。从机制上讲，降低 NELF-A 水平有助于暂停的 RNAPII 释放，从而进行热休克蛋白（Hsp）基因的有效转录。升高的 HSPs 表达反过来又减轻了衰老 NELF-A 耗尽果蝇大脑中不可溶蛋白聚集体、活性氧物质、DNA 损伤和全身炎症的积累，与它们的对照兄弟姐妹相比。由于其更高的表达水平和比其他 NELF 亚基更有效地暂停 RNAPII，这种延长寿命的效应是 NELF-A 所特有的。重要的是，NELF-A 杂合突变体对氧化应激的增强抗性高度保守，以至于敲低其在人 SH-SY5Y 细胞中的水平可减轻过氧化氢诱导的 DNA 损伤和细胞凋亡。NELF-A 的耗竭通过在衰老过程中维持富含 H3K9me2 的异染色质来重新配置表观基因组，导致特定逆转录转座子（如 Gypsy-1）在 NELF-A 突变体大脑中的抑制。总之，我们表明神经元 NELF-A 的剂量通过调节大脑中 Hsp 基因的转录来影响果蝇的多个衰老方面，表明靶向转录延伸可能是治疗神经退行性等与年龄相关疾病的可行治疗策略。
