Abstract
During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Here we set out to identify enhancers involved in the initial events of cardiogenesis, which occurs during the phylotypic period. We isolate early cardiac progenitor cells from zebrafish embryos and characterize 3838 open chromatin regions specific to this cell population. Of these regions, 162 overlap with conserved non-coding elements (CNEs) that also map to open chromatin regions in human. Most of the zebrafish conserved open chromatin elements tested drive gene expression in the developing heart. Despite modest sequence identity, human orthologous open chromatin regions recapitulate the spatial temporal expression patterns of the zebrafish sequence, potentially providing a basis for phylotypic gene expression patterns. Genome-wide, we discover 5598 zebrafish-human conserved open chromatin regions, suggesting that a diverse repertoire of ancient enhancers is established prior to organogenesis and the phylotypic period.
Highlights
During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms
We find that these conserved accessible chromatin elements were highly associated with developmental transcription factors that are regulated by polycomb repressive complex 2 (PRC2)
We found that the Smarcd3-F6 region was enriched for the active enhancer mark H3K27ac and contains a cis-regulatory elements (CREs) co-bound by several conserved cardiac transcription factors (TFs) (GATA4, NKX2.5, TBX5) in mouse embryonic stem cells (ESCs) differentiated cardiac precursors (CP) and cardiomyocytes (CM)[18,21] (Supplementary Fig. 1a)
Summary
Embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Distinct subtypes of mouse cardiac progenitors emerge within the gastrula stage preceding the expression of the canonical cardiac progenitor marker Nkx2.5, long before any organ structure is formed[12,13,14] How this potential early cardiac specification is controlled by enhancer elements, and the extent to which this process is evolutionarily conserved, is not known. Analysis of putative enhancers in mesoderm cells, derived from embryonic stem cells, show higher evolutionary constraint than the enhancers identified after organogenesis[8] This suggests that the regulatory elements that establish the conserved cardiac transcriptional program may exist at the initial stages of heart development, presumptively during the time window from naive mesoderm to cardiac progenitors
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