Lung lineage transcription factor NKX2-1 epigenetically resolves opposing cell fates in vivo

Abstract

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

Endodermal BRD4 mediates epithelial-mesenchymal crosstalk during lung development

“…[1][2][3][4] Lung morphogenesis additionally relies on epigenetic factors, such as DNA methyltransferases, histone modification enzymes, and noncoding RNAs, to ensure the proper epithelial lineage specification, proliferation, and maturation necessary to generate a functional lung. [5][6][7][8][9][10][11][12][13][14] Epithelial cell fate decisions occur in a spatially specific manner and are major drivers of not only lung development but also adult regeneration after injury. [15][16][17] The ability of epigenetic factors to manipulate epithelial cell fate has made them attractive targets for amelioration of human disease, but our understanding of these factors remains limited.…”