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<p>Transcription factor (TF) dosage represents an overlooked aspect of developmental regulation. While Gata3 has traditionally been viewed as a determinant of trophectoderm (TE), its potential role in primitive endoderm (PE) has remained unclear. Here, we demonstrate that Gata3 functions as a dosage-sensitive regulator directing mutually exclusive lineage programs in mouse embryonic stem (ES) cells. Low levels of Gata3 (Gata3-L) promote PE-like transcriptional states, while high levels (Gata3-H) drive TE identity by rapidly repressing pluripotency and inducing TE markers. Genome-wide binding analysis reveals a dose-dependent redistribution of Gata3 across enhancers, with chromatin engagement consistent with pioneer factor-like activity. Functional 3D blastoid assays combined with single-cell transcriptomics further establish that Gata3 dosage alone is sufficient to instruct the spatial segregation of PE- versus TE-like compartments. These findings redefine Gata3 not merely as a TE determinant but as a central dosage-sensitive switch in lineage specification. More broadly, our results position TF dosage as a fundamental regulatory parameter that integrates enhancer selection, chromatin engagement, and spatial patterning, providing new opportunities to refine stem cell-based models and engineer developmental outcomes.</p>

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Gata3 dosage governs primitive endoderm versus trophectoderm specification in embryonic stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Yeejin Jang,
  • Mijeong Kim,
  • Joonhyuk Choi,
  • Jonghwan Kim

摘要

Transcription factor (TF) dosage represents an overlooked aspect of developmental regulation. While Gata3 has traditionally been viewed as a determinant of trophectoderm (TE), its potential role in primitive endoderm (PE) has remained unclear. Here, we demonstrate that Gata3 functions as a dosage-sensitive regulator directing mutually exclusive lineage programs in mouse embryonic stem (ES) cells. Low levels of Gata3 (Gata3-L) promote PE-like transcriptional states, while high levels (Gata3-H) drive TE identity by rapidly repressing pluripotency and inducing TE markers. Genome-wide binding analysis reveals a dose-dependent redistribution of Gata3 across enhancers, with chromatin engagement consistent with pioneer factor-like activity. Functional 3D blastoid assays combined with single-cell transcriptomics further establish that Gata3 dosage alone is sufficient to instruct the spatial segregation of PE- versus TE-like compartments. These findings redefine Gata3 not merely as a TE determinant but as a central dosage-sensitive switch in lineage specification. More broadly, our results position TF dosage as a fundamental regulatory parameter that integrates enhancer selection, chromatin engagement, and spatial patterning, providing new opportunities to refine stem cell-based models and engineer developmental outcomes.