RT Journal
A1 Pawlak, Michal
A1 Kedzierska, Katarzyna Z.
A1 Migdal, Maciej
A1 Nahia, Karim Abu
A1 Ramilowski, Jordan A.
A1 Bugajski, Lukasz
A1 Hashimoto, Kosuke
A1 Marconi, Aleksandra
A1 Piwocka, Katarzyna
A1 Carninci, Piero
A1 Winata, Cecilia L.
T1 Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development
JF Genome Research 
JO Genome Research 
YR 2019 
FD March 01 
VO 29 
IS 3 
SP 506 
OP 519 
DO 10.1101/gr.244491.118 
UL http://genome.cshlp.org/content/29/3/506.abstract 
AB 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.