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|Public on Dec 01, 2023
|Distinct epicardial gene regulatory programmes drive development and regeneration of the zebrafish heart
|Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|Unlike the adult mammalian heart, which has limited regenerative capacity, the zebrafish heart can fully regenerate following injury. Reactivation of cardiac developmental programmes is considered key to successfully regenerating the heart, yet the regulatory elements underlying the response triggered upon injury and during development remain elusive. Organ-wide activation of the epicardium is essential for zebrafish heart regeneration and is considered a potential regenerative source to target in the mammalian heart. Here we compared the transcriptome and epigenome of the developing and regenerating zebrafish epicardium by integrating gene expression profiles with open chromatin ATAC-seq data. We identified epicardial enhancer elements with specific activity during development or during adult heart regeneration. By generating gene regulatory networks associated with epicardial development and regeneration, we inferred genetic programmes driving each of these processes, which were largely distinct. We identified Wt1a, Wt1b, and the AP-1 subunits Junbb, Fosab and Fosb as central regulators of the developing network, whereas Hif1ab, Nrf1, Tbx2b and Zbtb7a featured as putative central regulators of the regenerating epicardial network. Targeting hif1ab, nrf1, tbx2b and zbtb7a using CRISPR/Cas9 in injured hearts resulted in elevated epicardial cell numbers infiltrating the wound and excess fibrosis after cryoinjury, illustrating the functional importance of these regulatory factors during zebrafish heart regeneration. Our work reveals striking differences between the regulatory blueprint deployed during epicardial development and regeneration. These findings underline that heart regeneration goes beyond the reactivation of developmental programmes and provide important insights into epicardial regulation.
|Bulk ATAC and RNA sequencing of purified zebrafish epicardial cells, either at 5 days-post-fertilization or at 3 days-post-cryoinjury or at 3 days-post-sham
|Weinberger M, Simoes FC, Gungoosingh T, Sauka-Spengler T, Riley PR
|Jun 23, 2021
|Last update date
|Dec 01, 2023
|Paul Richard Riley
|University of Oxford
|IMS-Tetsuya Nakamura Building, Old Road Campus
|Illumina NextSeq 500 (Danio rerio)
|SRA Run Selector