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NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [ChIP-seq]

ABSTRACT: Comparison of differential H3K9me2 enrichment in Day 50 adult heterozygous NELF-A*/+ mutant (BX) and control sibling (Sib) fly heads (2 biological replicates).

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE155938 | GEO | 2020/11/30

REPOSITORIES: GEO

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NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [RNA-seq]

Project description:Comparison of differentially expressed genes in Day 50 adult heterozygous NELF-A*/+ mutant (BX) and control sibling (Sib) fly heads (2 replicates).

2020-11-30 | GSE155939 | GEO

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance

Project description:Epigenetic alteration is a hallmark of aging, but it remains unclear if perturbation of transcription machineries may affect longevity. NELF-mediated pausing of RNA polymerase II (RNAPII) constitutes an important step in transcription regulation. We found that halving NELF-A level in heterozygous mutants or via neuronal-specific depletion of NELF-A improves locomotor activity, stress resistance and lifespan of Drosophila significantly. Mechanistically, lower NELF-A releases paused RNAPII to facilitate productive transcription of the heat-shock protein (Hsp) genes. Elevated HSPs attenuate the level of protein aggregation, reactive oxidative species, DNA damage and systemic inflammation in the brains of NELF-A depleted flies. This protection is conserved in human cells where NELF-A depletion confers improved resistance against oxidative stress. Reduced oxidative DNA damage allows the maintenance of H3K9me2-enriched heterochromatin, which represses the activation of specific retrotransposons during aging. Therefore, by regulating transcription of Hsp genes in the brains, NELF-A controls multiple aspects of aging in Drosophila.

2020-11-30 | GSE155940 | GEO

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance.

Project description: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.

| S-EPMC8135010 | biostudies-literature

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance

Project description:NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance

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NELF-A phosphorylation site identification

Project description:NELF-A phosphorylation by P-TEFb is a key event in the pausing release. We conduct IMAC-LC-MS-MS to identified NELF-A phosphorylation site by activation P-TEFb kinase.

2016-03-23 | PXD003433 | Pride

NELF-dependent transcription activation

Project description:Jurkat T-cells were latently infected with a defective HIV provirus carrying a GFP reporer gene. The cells were superinfected with a lentiviral vector expressing shRNA to NELF-E. The impact of NELF-depletion on RNAP II distribution on cellular genes and the HIV provirus was measured by ChIP-Seq. Data sets contained between 45 and 56 million mapped reads Four samples were compared: Control shRNA, NELF-E shRNA, Control shRNA plus TNF-a, NELF-E shRNA plus TNF-a.

2014-03-26 | E-GEOD-47481 | biostudies-arrayexpress

Heart tissue from Nelf-b CreER mice

Project description:Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here we show for the first time that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptors alpha (PPARalpha), a master regulator of energy metabolism in myocardium. Mechanistically, NELF helps stablize the transcription initation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARalpha-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes. 3 Nelf-b f/f and 3 Nelf-b f/f; CreER female mice were injected with Tamoxifen at 8 wk old. Heart tissue were harvested at 20 wks old and used for RNA preparation.

2014-03-01 | E-GEOD-54372 | biostudies-arrayexpress

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [ChIP-seq]

Project description:NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [ChIP-seq]

| PRJNA656367 | ENA

NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [RNA-seq]

Project description:NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance [RNA-seq]

| PRJNA656368 | ENA

Heart tissue from Nelf-b CreER mice

2014-03-01 | GSE54372 | GEO