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

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 () and Xinhua Lin ()
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Shenfei Sun: Inner Mongolia University, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences
Yamei Jiang: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Fujing Huang: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Wei Wei: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Mathias Hochgerner: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Tianmin Xu: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Xiaoting Wang: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Kaijun Lin: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Xinna Zhang: Inner Mongolia University, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences
Yanli Wang: Inner Mongolia University, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences
Hua He: Sichuan University and School of Life Sciences of Fudan University, The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital
Miao Yu: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences
Xiaofang Tang: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital
Xinhua Lin: Inner Mongolia University, State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65757-1

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