Please use this identifier to cite or link to this item:
Title: NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance
Authors: Ngian, Zhen-Kai
Lin, Wei-Qi
Ong, Chin-Tong 
Keywords: Drosophila
heat-shock proteins
stress responses
Issue Date: 31-Mar-2021
Publisher: John Wiley and Sons Inc
Citation: Ngian, Zhen-Kai, Lin, Wei-Qi, Ong, Chin-Tong (2021-03-31). NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance. Aging Cell 20 (5) : e13348. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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. © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Source Title: Aging Cell
ISSN: 1474-9718
DOI: 10.1111/acel.13348
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1111_acel_13348.pdf2.49 MBAdobe PDF



Google ScholarTM



This item is licensed under a Creative Commons License Creative Commons