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Comprehensive model illustrating the stepwise, EOMES-dependent chromatin remodeling that rewires pluripotent cells from their default NE differentiation path toward a ME-lineage-competent state. In primed pluripotent cells, enhancers of ME program genes are in largely closed chromatin conformation and lightly pre-marked by H3K4me1. During initiation of ME specification, the Tbx TFEomesis expressed, and in cooperation with canonical SWI/SNF globally binds to enhancers of ME program genes. This enhancer recruitment is crucial to generate initial enhancer accessibility that is used and further stabilized by signal-activated transcriptional regulators of ME lineage-specific gene programs, e.g., β-catenin, TCF, or SMAD2/3 and ME-specific TFs leading to transcriptional onset. See alsoFigure S7andTable S4.

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