Abstract

Regeneration is an endogenous process of tissue repair that culminates in complete restoration of tissue and organ function. While regenerative capacity in mammals is limited to select tissues, lower vertebrates like zebrafish and salamanders are endowed with the capacity to regenerate entire limbs and most adult tissues, including heart muscle. Numerous profiling studies have been conducted using these research models in an effort to identify the genetic circuits that accompany tissue regeneration. Most of these studies, however, are confined to an individual injury model and/or research organism and focused primarily on protein encoding transcripts. Here we describe RegenDbase, a new database with the functionality to compare and contrast gene regulatory pathways within and across tissues and research models. RegenDbase combines pipelines that integrate analysis of noncoding RNAs in combination with protein encoding transcripts. We created RegenDbase with a newly generated comprehensive dataset for adult zebrafish heart regeneration combined with existing microarray and RNA-sequencing studies on multiple injured tissues. In this current release, we detail microRNA–mRNA regulatory circuits and the biological processes these interactions control during the early stages of heart regeneration. Moreover, we identify known and putative novel lncRNAs and identify their potential target genes based on proximity searches. We postulate that these candidate factors underscore robust regenerative capacity in lower vertebrates. RegenDbase provides a systems-level analysis of tissue regeneration genetic circuits across injury and animal models and addresses the growing need to understand how noncoding RNAs influence these changes in gene expression.

Highlights

  • A limited capacity to repair and regenerate injured and damaged tissues underscores many degenerative and chronic diseases.[1,2,3,4] Regenerative biology seeks to define endogenous and fundamental mechanisms that can be used to stimulate human regenerative capacity

  • Employing the RegenDbase functionality for analyses of RNA-sequencing dataset across zebrafish heart regeneration, we identified a subset of previously annotated lncRNAs that were differentially expressed during 1 and Identification of novel lncRNAs expressed during early stages of zebrafish heart regeneration We applied an analysis workflow to identify potential novel

  • We designed and built RegenDbase to facilitate the comparison of diverse regenerative models with a unique focus on noncoding RNAs, critical regulators of regeneration signaling pathways at multiple levels of gene expression

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Summary

Introduction

A limited capacity to repair and regenerate injured and damaged tissues underscores many degenerative and chronic diseases.[1,2,3,4] Regenerative biology seeks to define endogenous and fundamental mechanisms that can be used to stimulate human regenerative capacity. The zebrafish, Danio rerio, can regenerate multiple adult tissues including cardiac,[5] spinal cord,[6] and fin appendages.[7] Urodele models of limb regeneration include the axolotl (Ambystoma mexicanum)[8] and newt (Notophtalmus viridescens).[9] Studies of these individual models have advanced our understanding of regeneration genetic circuits and their regulation. Among these mechanisms are microRNAs (miRNAs), small noncoding RNAs that are essential regulators of development and adult tissue regeneration.[10,11,12,13]

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