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<p>Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the <i>Ctcf</i> conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.</p>

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Single-cell multiomics analysis reveals CTCF as a key regulator of lung morphogenesis and progenitor maintenance

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月28日

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  • Shenfei Sun,
  • Yamei Jiang,
  • Fujing Huang,
  • Wei Wei,
  • Mathias Hochgerner,
  • Tianmin Xu,
  • Xiaoting Wang,
  • Kaijun Lin,
  • Xinna Zhang,
  • Yanli Wang,
  • Hua He,
  • Miao Yu,
  • Xiaofang Tang,
  • Xinhua Lin

摘要

Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.