Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development

  1. Cecilia L. Winata1,4
  1. 1International Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental Genomics, 02-109 Warsaw, Poland;
  2. 2RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Japan;
  3. 3Nencki Institute of Experimental Biology, Laboratory of Cytometry, 02-093 Warsaw, Poland;
  4. 4Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
  • Corresponding author: cwinata{at}iimcb.gov.pl
  • Abstract

    Organogenesis involves dynamic regulation of gene transcription and complex multipathway interactions. Despite our knowledge of key factors regulating various steps of heart morphogenesis, considerable challenges in understanding its mechanism still exist because little is known about their downstream targets and interactive regulatory network. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption in vivo, we performed time-series analyses of the transcriptome and genome-wide chromatin accessibility in isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at developmental stages corresponding to heart tube morphogenesis, looping, and maturation. We identified genetic regulatory modules driving crucial events of heart development that contained key cardiac TFs and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. Loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile, indicating their role in heart development. Among regions with differential chromatin accessibility in mutants were highly conserved noncoding elements that represent putative enhancers driving heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart tube morphogenesis and looping, and were associated with metabolic shift and hematopoietic/cardiac fate switch during CM maturation. Our results revealed the dynamic regulatory landscape throughout heart development and identified interactive molecular networks driving key events of heart morphogenesis.

    Footnotes

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.244491.118.

    • Freely available online through the Genome Research Open Access option.

    • Received September 21, 2018.
    • Accepted January 9, 2019.

    This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

    | Table of Contents
    OPEN ACCESS ARTICLE

    Preprint Server