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

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. In C. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robu...

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Main Authors:	Pandit, Awadhesh, Jain, Vaibhav, Kumar, Neeraj, Mukhopadhyay, Arnab
Format:	Online
Language:	English
Published:	Impact Journals LLC 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247386/

id	pubmed-4247386
recordtype	oai_dc
spelling	pubmed-42473862014-12-08 PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction Pandit, Awadhesh Jain, Vaibhav Kumar, Neeraj Mukhopadhyay, Arnab Research Paper 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. In C. 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. Impact Journals LLC 2014-10-31 /pmc/articles/PMC4247386/ /pubmed/25504288 Text en Copyright: © 2014 Pandit et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Pandit, Awadhesh Jain, Vaibhav Kumar, Neeraj Mukhopadhyay, Arnab
spellingShingle	Pandit, Awadhesh Jain, Vaibhav Kumar, Neeraj Mukhopadhyay, Arnab PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
author_facet	Pandit, Awadhesh Jain, Vaibhav Kumar, Neeraj Mukhopadhyay, Arnab
author_sort	Pandit, Awadhesh
title	PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
title_short	PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
title_full	PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
title_fullStr	PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
title_full_unstemmed	PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction
title_sort	pha-4/foxa-regulated microrna feed forward loops during caenorhabditis elegans dietary restriction
description	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. In C. 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.
publisher	Impact Journals LLC
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247386/
_version_	1613161868467109888

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

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