Center for Developmental Genetics, Department of Biology, New York University, New York, United States.
Elife. 2019 Nov 20;8:e49921. doi: 10.7554/eLife.49921.
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 to profile chromatin accessibility through stereotyped transitions from naive + 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 -regulatory elements, with distinct chromatin accessibility profiles and motif compositions, are required to activate and , 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.
在胚胎发生过程中，染色质可及性图谱通过调节转录来控制谱系特异性基因表达，从而影响多能祖细胞状态和随后的命运选择。心脏和咽/头肌肉的亚群在心脏咽中胚层中具有共同的起源，但控制多能祖细胞能力和早期命运选择的染色质景观在很大程度上仍难以捉摸。在这里，我们利用脊索动物模型的简单性，通过从原始 + 中胚层到不同命运受限的心脏和咽肌肉前体的定型过渡来描绘染色质可及性。FGF-Foxf 途径在多能祖细胞中起作用，以建立心脏咽特异性的可及性模式，该模式决定了后期心脏与咽肌肉特异性表达谱，证明了早期心脏咽增强子可及性和晚期细胞类型特异性活性之间存在广泛的时空解耦。我们发现，多个具有不同染色质可及性图谱和基序组成的 - 调控元件，对于激活 和 是必需的，这是心脏咽命运选择的两个关键决定因素。我们提出，这些“组合增强子”通过增加控制基因表达的调控输入的 repertoire，通过可及性和/或活性，促进空间和时间上准确的命运选择。
