4.7 Article

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

Journal

DEVELOPMENT
Volume 149, Issue 4, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200133

Keywords

Epicardium; Enhancer; TREE; Heart regeneration; Zebrafish; ATAC-seq

Funding

  1. Rudin Foundation Fellowship
  2. National Institutes of Health (NIH) [R01HL131319, R35HL150713]
  3. American Heart Association Merit Award
  4. American Heart Association Career Development Award [18CDA34110108]
  5. Weill Cornell Start-up fund
  6. National Institutes of Health [R01HL155607]

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The study identified tissue regeneration enhancer elements (TREEs) that control epicardial gene expression during heart regeneration. Through transcriptome and chromatin accessibility analysis of epicardial cells in regenerating zebrafish hearts, hundreds of candidate TREEs were discovered and their functions in heart regeneration were validated. These findings provide important insights into the regulation of epicardial genetic programs during heart regeneration.
The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which in zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify tissue regeneration enhancer elements (TREEs) that control injury induced epicardial gene expression during heart regeneration, we profiled transcriptomes and chromatin accessibility in epicardial cells purified from regenerating zebrafish hearts. We identified hundreds of candidate TREEs, which are defined by increased chromatin accessibility of non-coding elements near genes with increased expression during regeneration. Several of these candidate TREEs were incorporated into stable transgenic lines, with five out of six elements directing injury-induced epicardial expression but not ontogenetic epicardial expression in larval hearts. Whereas two independent TREEs linked to the gene gnai3 showed similar functional features of gene regulation in transgenic lines, two independent ncamla-linked TREEs directed distinct spatiotemporal domains of epicardial gene expression. Thus, multiple TREEs linked to a regeneration gene can possess either matching or complementary regulatory controls. Our study provides a new resource and principles for understanding the regulation of epicardial genetic programs during heart regeneration. This article has an associated 'The people behind the papers' interview.

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