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Integrative Single-Cell Analysis of Gene Expression and Chromatin Accessibility Reveals CTCF as a Key Regulator of Stem Cell Differentiation and Lung Morphogenesis [scRNA-seq]

ABSTRACT: The lungs develop into an intricate tree-like structure through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs that dictate embryonic lung development remain largely unclear. Here, we profile gene expression and chromatin accessibility in mouse embryonic lungs to generate a multi-omics atlas at single-cell resolution. By integrative analyses, we dissect 10 cell type-specific gene expression signatures and characterize177,990 cis-regulatory elements (CREs), 36,114 differential accessible chromatin regions (DARs), 27,628 gene-to-peak linkages, 632 highly regulated genes (HRGs), and their binding transcription factors (TFs). We also explore candidate regulators driving lung progenitor developmental trajectory and discover the important role of the AP-1 complex in mesenchymal differentiation. Based on this multi-modal dataset, we delineate gene regulatory networks (GRNs) across various cell types. Finally, using the Ctcf conditional knockout mouse model combined with multiple approaches, we reveal CTCF as a crucial regulator of Sox2+ progenitor specification and lung branching morphogenesis by reprogramming transcriptome and chromatin accessibility. Therefore, this study provides multi-omics resources and mechanistic insights for transcription regulation of lung morphogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE286985 | GEO | 2025/11/13

REPOSITORIES: GEO

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Integrative Single-Cell Analysis of Gene Expression and Chromatin Accessibility Reveals CTCF as a Key Regulator of Stem Cell Differentiation and Lung Morphogenesis [multi-omics]

Project description:The lungs develop into an intricate tree-like structure through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs that dictate embryonic lung development remain largely unclear. Here, we profile gene expression and chromatin accessibility in mouse embryonic lungs to generate a multi-omics atlas at single-cell resolution. By integrative analyses, we dissect 10 cell type-specific gene expression signatures and characterize177,990 cis-regulatory elements (CREs), 36,114 differential accessible chromatin regions (DARs), 27,628 gene-to-peak linkages, 632 highly regulated genes (HRGs), and their binding transcription factors (TFs). We also explore candidate regulators driving lung progenitor developmental trajectory and discover the important role of the AP-1 complex in mesenchymal differentiation. Based on this multi-modal dataset, we delineate gene regulatory networks (GRNs) across various cell types. Finally, using the Ctcf conditional knockout mouse model combined with multiple approaches, we reveal CTCF as a crucial regulator of Sox2+ progenitor specification and lung branching morphogenesis by reprogramming transcriptome and chromatin accessibility. Therefore, this study provides multi-omics resources and mechanistic insights for transcription regulation of lung morphogenesis.

2025-11-13 | GSE286981 | GEO

Single-cell Multiomics Analysis Reveals CTCF as a Key Regulator of Lung Morphogenesis and Progenitor Maintenance

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Acute depletion of CTCF rewires genome-wide chromatin accessibility

Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation

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