title: 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.
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Awadhesh
authors.initials: A
authors.lastname: Pandit
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jain
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D031204:Caloric Restriction; D005786:Gene Expression Regulation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D008136:Longevity / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015534:Trans-Activators / Q000235:genetics*; D059467:Transcriptome
chemical_list: D029742:Caenorhabditis elegans Proteins; D035683:MicroRNAs; C113277:Pha-4 protein, C elegans; D015534:Trans-Activators