A molecular circuit regulates fate plasticity in emerging and adult AT2 cells [ATAC-seq]
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ABSTRACT:
PROVIDER: PRJNA1261056 | ENA |
REPOSITORIES: ENA
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Project description:Alveolar AT1 and AT2 cells are vital for gas exchange in the lung and become compromised in several common and deadly diseases. While the signals driving differentiation of either cell type have been identified, it remains unclear when and how fate plasticity is regulated in the emerging and adult alveolar epithelium. Here we show AT2s first emerge as singletons at zones between the proximal stalks and distal tips of the embryonic lung that quickly extrude and can traverse the interstitium to connect with nearby epithelium, a process we term interlumenal junctioning. Throughout the late embryonic and early perinatal period, we find that a window of AT2 fate plasticity exists that is closed by the bZIP transcription factor C/EBPα, mediated by its transcriptional suppression of the Notch signaling regulator DLK1. C/EBPα acts on Dlk1 at a novel regulatory site. Further, both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), and together constitute a novel incoherent feedforward loop that generates a Dlk1 pulse upon downregulation of PRC2. We propose these form a “pulse generator” circuit capable of generating a timed activation of Notch signaling, resulting in a “salt and pepper” pattern of AT1 and AT2 fate. Following injury in the adult lung, we found that C/EBPα downregulation is required for re-accessing AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, we observe Cebpa loss also activates a “defender” AT2 state enriched in interferon-stimulated antipathogenic gene expression that is distinct from its reparative state and propose AT2s toggle between these states following infection to robustly protect and repair alveoli.
2025-07-30 | GSE295269 | GEO
Project description:Alveolar AT1 and AT2 cells are vital for gas exchange in the lung and become compromised in several common and deadly diseases. While the signals driving differentiation of either cell type have been identified, it remains unclear when and how fate plasticity is regulated in the emerging and adult alveolar epithelium. Here we show AT2s first emerge as singletons at zones between the proximal stalks and distal tips of the embryonic lung that quickly extrude and can traverse the interstitium to connect with nearby epithelium, a process we term interlumenal junctioning. Throughout the late embryonic and early perinatal period, we find that a window of AT2 fate plasticity exists that is closed by the bZIP transcription factor C/EBPα, mediated by its transcriptional suppression of the Notch signaling regulator DLK1. C/EBPα acts on Dlk1 at a novel regulatory site. Further, both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), and together constitute a novel incoherent feedforward loop that generates a Dlk1 pulse upon downregulation of PRC2. We propose these form a “pulse generator” circuit capable of generating a timed activation of Notch signaling, resulting in a “salt and pepper” pattern of AT1 and AT2 fate. Following injury in the adult lung, we found that C/EBPα downregulation is required for re-accessing AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, we observe Cebpa loss also activates a “defender” AT2 state enriched in interferon-stimulated antipathogenic gene expression that is distinct from its reparative state and propose AT2s toggle between these states following infection to robustly protect and repair alveoli.
2025-08-23 | GSE296786 | GEO
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Project description:Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity where Cebpa mutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.
2024-04-18 | GSE247130 | GEO
Project description:Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity where Cebpa mutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.
2024-04-16 | GSE264098 | GEO
Project description:Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity where Cebpa mutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.
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