Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo

Abstract Differential transcription of identical DNA sequences leads to distinct tissue lineages and then multiple cell types within a lineage, an epigenetic process central progenitor stem biology. The associated genome-wide changes, especially in native tissues, remain insufficiently understood, are hereby addressed the mouse lung, where same lineage factor NKX2-1 promotes diametrically opposed alveolar type 1 (AT1) AT2 fates. Here, we report that cell-type-specific function is attributed its differential chromatin binding acquired or retained during development coordination with partner transcriptional factors. Loss YAP/TAZ redirects from AT1-specific AT2-specific sites, leading transcriptionally exaggerated cells when deleted progenitors AT1-to-AT2 conversion after fate commitment. Nkx2-1 mutant AT1 gain accessible including those specific opposite while adopting gastrointestinal fate, suggesting plasticity unexpected changes. Our genomic analysis single purified cells, coupled precision genetics, provides basis for potential, introduces experimental benchmark deciphering vivo