Dataset Information

PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction.

ABSTRACT: Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. InC. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation sequencing and find that most of the miRNAs are upregulated in the young-adult worms, none significantly downregulated. Interestingly, PHA-4 can potentially regulate the expression of most of these miRNA genes. Remarkably, many of the PHA-4-regulated genes that are induced during DR are also targets of the PHA-4-upregulated miRNAs, forming a large feed-forward gene regulatory network. The genes targeted by the feed-forward loops (FFLs) are enriched for functions related to ubiquitin-mediated decay, lysosomal autophagy, cellular signalling, protein folding etc., processes that play critical roles in DR and longevity. Together our data provides a framework for understanding the complex and unique regulatory network employed during DR, suggesting that PHA-4 employs such FFLs to fine-tune gene expression and instil robustness in the system during energy crisis.

SUBMITTER: Pandit A

PROVIDER: S-EPMC4247386 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction.

Pandit Awadhesh A Jain Vaibhav V Kumar Neeraj N Mukhopadhyay Arnab A

Aging 20141001 10

Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. InC. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation ...[more]

PMID: 25504288

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Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway. Experiment Overall Design: We examined fasting-induced changes of the gene expression profiles in Caenorhabditis elegans. We performed the genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays, and examined the effect of downregulation of Cel-Rheb and Cel-TOR by RNAi on the expression profiles. Five independent experiments were performed with wild type N2. Synchronized worms under six conditions (control-fed, control-fasting, Rheb RNAi-fed, Rheb RNAi-fasting, TOR RNAi-fed, and TOR RNAi-fasting) were collected and frozen with liquid nitrogen at day 4 of adulthood. Total RNA was extracted with Sepasol(R)-RNA â Super (Nacalai tesque), and purified with RNeasy Mini Kit (Qiagen), according to manufactureâs instructions. Synthesis of cDNA, in vitro transcription and biotin labelling cRNA, and hybridization to the C. elegans Genome Array (Affymetrix) were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned chip images were analyzed with GeneSpring GX 7.3.1 (Agilent Technologies).

Dataset Information

PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction.

Publications

PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction.

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