A molecular circuit regulates fate plasticity in emerging and adult AT2 cells [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1253980 | 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.
2025-08-23 | GSE296786 | 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.
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Project description:Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In line with patient data, PROX1 overexpression in mice blocked initiation and progression of hepatocellular carcinoma and extended survival. Remarkably, Prox1 depletion caused hepatocyte fate loss in vitro, and promoted transdifferentiation of hepatocellular- to cholangio-carcinoma in vivo. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.
2024-11-11 | PXD053043 | Pride
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.
2024-04-19 | GSE247271 | 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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Project description:RNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease (NMD). How the timing of RBP function governs the complex cell fate decisions during muscle regeneration is poorly understood. Here, single cell analysis of skeletal muscle regeneration reveals the timing of NMD-associated RBPs expression in muscle progenitors, including a massive upregulation of Hnrnpa2b1 (A2b1). A2b1 promotes muscle progenitor plasticity by regulating the splicing of RNAs expressed at specific times during the trajectory of muscle differentiation. Using RBP-RNA engagement scoring and machine learning, we accurately predict NMD-associated RBP functionality in directing myogenesis. Together our analysis reveals how A2b1 regulates myogenic plasticity and provides a broadly applicable single cell methodology for examining how RBPs influence complex cell fate trajectories.
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