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Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices.

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.

SUBMITTER: Racioppi C

PROVIDER: S-EPMC6952182 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices.

Racioppi Claudia C Wiechecki Keira A KA Christiaen Lionel L

eLife 20191120

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 <i>Ciona</i> to pro ...[more]

PMID: 31746740

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Project description:Gene regulation often appears deterministic in the average cell population, but transcription is a probabilistic process at the single-cell level. Although many mechanisms are invoked to account for this behavior, it is difficult to determine how cell-to-cell variation in the interactions of transcription factors with target chromatin impact transcriptional output. Here, we use cells that contain a 200-copy tandem array of promoter or reporter gene units to simultaneously visualize transient interaction, equilibrium or steady-state binding of fluorescent-protein-labeled glucocorticoid receptor with its DNA response elements, the recruitment of diverse coregulators, and transcriptional output at the single-cell level. These regulatory proteins associate with target chromatin via a probabilistic mechanism that produces cell-to-cell variability in binding. The multiple steps of this process are partially independent and differ between individual regulators. The association level of each regulator influences the transcriptional output in individual cells, but this does not account for all transcriptional heterogeneity. Additionally, specific combinatorial interactions of the glucocorticoid receptor and coregulators with response elements regulate transcription at the single-cell level. Like many endogenous genes, the average array transcriptional activity evolves over time. This apparently deterministic average temporal promoter progression involves changes in the probability that specific combinatorial glucocorticoid receptor and coregulator interactions will occur on the response elements in single cells. These data support the emerging ;return-to-template' transcription model, which mechanistically unifies the observed extremely transient interactions between the transcription factor and response elements, cell-to-cell variability in steady-state association of factors with chromatin, and the resulting heterogeneous gene expression between individual cells.

Dataset Information

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices.

Publications

Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices.

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