Project description:The nuclear chromatin landscape changes with age – a phenomenon observed across many species, including humans. Notably, perturbing this landscape can alter the rate of aging, indicating at least a partial role in controlling this process. This raises the question of whether chromatin alterations also distinguish animals that age at unusual rates. To explore this, we focused on insulin/IGF-like signaling (IIS) in Caenorhabditis elegans, a well-characterized signaling pathway whose impairment drastically slows aging and extends lifespan of these animals. Specifically, we conducted ATAC- and mRNA-seq in animals with reduced IIS (i.e., daf-2 mutants). Interestingly, we found that enhancer regions tend to close and become transcriptionally repressed with age, but under reduced IIS, they tend to open and become transcriptionally active, suggesting their potential relevance for lifespan regulation. By screening transcription factors (TFs) predicted to bind these regions, we identified the HOX gene LIN-39 as a novel aging-preventive TF required for the longevity of daf-2 mutants. LIN-39 performs this role specifically during development and in neurons. Further investigation showed that LIN-39 was acting around the L3 larval stage and in the hermaphrodite-specific VC class of cholinergic motor neurons – at a time when they undergo maturation. Finally, this LIN-39-dependent longevity required DAF-16/FOXO, a well-established aging-preventive TF that acts downstream of DAF-2, which may synergize with LIN-39 in VC neurons to open enhancer the regions. We ultimately propose a model whereby longevity of daf-2 mutant hermaphrodites requires a longevity-promoting signal emitted by VC neurons – a signal that relies on correct VC neuron maturation around the L3 stage, which in turn is assured by the actions of LIN-39 and resulting chromatin and gene expression changes. This renders LIN-39 a rare example of a developmental determinant of longevity. And given the conservation of IIS, HOX and FOXO TFs, and cholinergic neuron function across species, the here described mechanism may reflect a general principle by which developmental transcriptional programs shape adult longevity.

Project description:modENCODE_submission_2432 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP18(made_by : R. Waterston and S. Kim description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The LIN-39::EGFP fusion protein is expressed in the correct lin-39 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the LIN-39 transcription factor. tags : GFP::3xFlag mutagen : Bombard outcross : 3 genotype : unc-119(ed3) III; wgIs18 [unc-119(+) lin-39::TY1::EGFP::3xFLAG] official name : OP18 ); Developmental Stage: L3; Genotype: unc-119(ed3) III; wgIs18 [unc-119(+) lin-39::TY1::EGFP::3xFLAG]; Sex: Hermaphrodite; EXPERIMENTAL FACTORS: Developmental Stage L3; Target gene lin-39; Strain OP18(made_by : R. Waterston and S. Kim description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for biolistic transformation of an unc-119(ed3) strain. The LIN-39::EGFP fusion protein is expressed in the correct lin-39 spatio-temporal expression pattern. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the LIN-39 transcription factor. tags : GFP::3xFlag mutagen : Bombard outcross : 3 genotype : unc-119(ed3) III; wgIs18 [unc-119(+) lin-39::TY1::EGFP::3xFLAG] official name : OP18 ); temp (temperature) 20 degree celsius Series_type: CHIP-seq

Project description:Cholesterol has attracted significant attention as a possible lifespan regulator. It has been reported that serum cholesterol levels have an impact on mortality due to age-related disorders such as cardiovascular disease. Diet is also known to be an important lifespan regulator. Dietary restriction retards the onset of age-related diseases and extends lifespan in various organisms. Although cholesterol and dietary restriction are known to be lifespan regulators, it remains to be established whether cholesterol is involved in dietary restriction-induced longevity. Here, we show that cholesterol deprivation suppresses longevity induced by intermittent fasting, which is one of the dietary restriction regimens that effectively extend lifespan. We also found that cholesterol is required for the fasting-induced upregulation of transcriptional target genes such as the insulin/IGF-1 pathway effector DAF-16 and that cholesterol deprivation suppresses the long lifespan of the insulin/IGF-1 receptor daf-2 mutant. Remarkably, we found that cholesterol plays an important role in the fasting-induced nuclear accumulation of DAF-16. Moreover, knockdown of the cholesterol-binding protein NSBP-1, which has been shown to bind to DAF-16 in a cholesterol-dependent manner and to regulate DAF-16 activity, suppresses both fasting-induced longevity and DAF-16 nuclear accumulation. Furthermore, this suppression was not additive to the cholesterol deprivation-induced suppression, which suggests that NSBP-1 mediates, at least in part, the action of cholesterol to promote fasting-induced longevity and DAF-16 nuclear accumulation. These findings identify a novel role for cholesterol in the regulation of lifespan. Two independent replicates were performed. Total RNA was extracted with TRIzol (Invitrogen). The extracted RNA was purified with PureLink RNA Micro Kit (Invitrogen) and analyzed with Agilent 2100 Bioanalyzer to assess the RNA integrity. The microarray procedures were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner.

			Action	DRS
		Other
	SRR29767201.fastq.gz	Fastqsanger.gz
	SRR29767202.fastq.gz	Fastqsanger.gz
	SRR29767203.fastq.gz	Fastqsanger.gz
	SRR29767205.fastq.gz	Fastqsanger.gz

Dataset Information

LIN-39 functions as a neuron-specific developmental determinant of longevity in Caenorhabditis elegans with reduced insulin/IGF-like signaling [RNA-seq]

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