Project description:Upon severe injury to the lungs, a poorly understood multistep process results in either euplastic regeneration or dysplastic repair which leads to a loss of functional gas-exchanging alveolar tissue. We show that the dysplastic repair process consists of an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and Pdgfra-derived Pdgfrb+ mesenchymal cells, which proliferate and transit across multiple cells states before localizing to dysplastic regions. Temporal and spatial single cell analysis reveals that Pdgfra-derived Pdgfrb+ cells communicate via Notch signaling to dysplastic keratinized epithelium. Inactivation of proliferation and Notch signaling in these Pdgfra+ progenitor mesenchymal cells prevents the establishment of iTCHs. Mesenchymal Notch signaling in iTCHs suppresses Wnt and Fgf signaling, whereas loss of Notch rewires alveolar signaling patterns to promote euplastic regeneration and restore functional gas exchange in the lung. iTCH presence and signaling patterns can be used to differentially phenotype fibrotic from degenerative chronic lung disease, with associated apposing flows of FGF and WNT signaling discriminating these disease states. These data reveal the emergence of an injury and disease associated niche in the lung, its regulation by mesenchymal Notch signaling, and the impact these cellular decisions have on discriminating the choice between dysplastic repair or euplastic regeneration.
Project description:Temporal data on gene expression and context-specific open chromatin states can improve identification of key transcription factors (TFs) and the gene regulatory networks (GRNs) controlling cellular differentiation. However, their integration remains challenging. Here, we delineate a general approach for data-driven and unbiased identification of key TFs and dynamic GRNs, called EPIC-DREM. We generated time-series transcriptomic and epigenomic profiles during differentiation of mouse multipotent bone marrow stromal cells (MSCs) towards adipocytes and osteoblasts. Using our novel approach we constructed time-resolved GRNs for both lineages and identifed the shared TFs involved in both differentiation processes. To take an alternative approach to prioritize the identified shared regulators, we mapped dynamic super-enhancers in both lineages and associated them to target genes with correlated expression profiles. The combination of the two approaches identified aryl hydrocarbon receptor (AHR) and Glis family zinc finger 1 (GLIS1) as mesenchymal key TFs controlled by dynamic MSC-specific super-enhancers that become repressed in both lineages. AHR and GLIS1 control differentiation-induced genes and we propose they function as guardians of mesenchymal multipotency.
Project description:Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells.
Project description:Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells.
Project description:Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (scRNA-Seq)