Abstract
During embryogenesis, chromatin accessibility profiles control lineage-specific gene expression by modulating transcription, thus impacting multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. We found that multiple cis-regulatory elements, with distinct chromatin accessibility profiles and motif compositions, are required to activate Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that these 'combined enhancers' foster spatially and temporally accurate fate choices, by increasing the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity.
Highlights
How a species’ genome encodes its diverse and specific biological features has fascinated generations of biologists, and answers regarding the genetic control of body plan, organ, tissue and cell type formation have emerged from steady progress in developmental biology
To characterize the chromatin landscape underlying early cardiopharyngeal development, we used the assay for transposon-accessible chromatin (ATAC-seq; (Buenrostro et al, 2013)) on lineage-specific samples isolated at successive time points, and following defined perturbations (Figure 1A; Table S1; (Razy-Krajka et al, 2018a; Wang et al, 2019))
Using the B7.5 lineagespecific Mesp>tagRFP reporter (Wang et al, 2018), we used FACS to collect ~4,000 cells per biological replicate from embryos dissociated at five time points encompassing key transitions in cardiopharyngeal development (Figure 1A): naive Mesp+ mesoderm (aka founder cells; (Cooley et al, 2011), anterior tail muscles (ATMs), TVCs, second trunk ventral cells (STVCs) as well as fate-restricted first and second heart precursors (FHPs and SHPs), and pharyngeal muscle precursors (aka atrial siphon muscle founder cells ASMF- and their progeny, the ASM precursors -ASMP; (Razy-Krajka et al, 2014))
Summary
How a species’ genome encodes its diverse and specific biological features has fascinated generations of biologists, and answers regarding the genetic control of body plan, organ, tissue and cell type formation have emerged from steady progress in developmental biology. The ontogeny of diverse terminal cell identities involves differential expression of hundreds to thousands of genes. Their dynamic activities are orchestrated by complex gene regulatory networks, whereby DNA-binding proteins and cofactors act upon specific cis-regulatory elements to control gene expression (Davidson, 2010). Technical and conceptual revolutions in genome biology have extensively characterized the chromatin dynamics that govern the function of cis-regulatory elements (Klemm et al, 2019). As the nuclear genome is packaged in nucleosomes, DNA-binding transcription factors compete with histones to interact with cis-regulatory elements and control gene expression. The copyright holder for this preprint It is made available under transition from multipotent to fate restricted progenitors offers privileged insights into the genomic code for progressive cell type specification
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