AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair

Lynch, A. M.; Noun, T.; Yang, S.; Zhou, T.; Evans, S. E.; Kadara, H.; Chen, J.

doi:10.1101/2025.10.25.684549

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bioRxiv · 10.1101/2025.10.25.684549

AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair

Lynch, A. M.·Noun, T.·Yang, S.·Zhou, T.·Evans, S. E.·Kadara, H.·Chen, J.

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Abstract

Facultative stem cells including lung alveolar type 2 (AT2) cells must toggle between unipotent specialization at baseline and multipotent plasticity during injury-repair. The underlying molecular switches and epigenetic changes remain unclear yet dictate regenerative versus pathological outcomes. Using multiomics and mouse genetics, we show that AP-1 members FOS, FOSB, and JUNB promote an injury-induced transitional AT2 cell state and associated chromatin landscape. Joint transcriptomic-epigenomic profiling and immunostaining distinguish CLDN4+ AT2 cells as a KRT8high subset with open chromatin highly enriched for AP-1 motifs. JUNB and FOSB accumulate in these cells upon viral injury and, along with constitutive FOS, are required for CLDN4 induction, AT2 cell dispersion, and senescence signaling toward fibroblasts, while impacting region-specific alveolar type 1 (AT1) differentiation. AP-1 activation also occurs in mouse AT2 cells expressing oncogenic Kras and transitional cells in human lung tissues with premalignant or adenocarcinoma lesions. Our work refines AT2 transitional states and reveals a gene regulatory logic shared by tissue repair and tumorigenesis. SIGNIFICANCE STATEMENTFacultative stem cells balance between their resting mode and regenerative mode. In the lung, alveolar type 2 (AT2) cells produce surfactants at baseline and, upon injury, activate to self-renew and differentiate into alveolar type 1 (AT1) cells. Such activation, observed in acute lung injury, fibrosis, and tumorigenesis, proceeds through a high-KRT8 transitional phase. Using multiomic profiling and mouse genetics, we identify activator protein-1 (AP-1) transcription factors as central regulators of a CLDN4 transitional substate, promoting AT2 cell dispersion, fibroblast signaling, and region-specific AT1 differentiation. AP-1 activation is conserved during oncogenic transformation in both mouse and human lungs. These findings refine our understanding of AT2 cell fate transition and chromatin dynamics, and reinforce a molecular connection between alveolar repair and tumorigenesis.

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Lynch, A. M., Noun, T., Yang, S., Zhou, T., Evans, S. E., Kadara, H., Chen, J.. 2025-10-26. AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair. https://doi.org/10.1101/2025.10.25.684549

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