GSE210800
Dot1L regulates the rate of lung alveolar regeneration through control of oxidative phosphorylatio
Alveolar type 1 and type 2 cells comprise the epithelial component of the lung alveolus where gas exchange occurs. AT2 cells harbor progenitor activity and can self-renew and differentiate into AT1 cells during homeostasis and after injury. To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors. This screen identified Dot1L as a potential regulator of AT2 growth and differentiation. To explore the role of Dot1L in vivo, we genetically inactivated Dot1L during lung development, showing that this leads to precocious activation of both AT1 and AT2 gene expression. Loss of Dot1L in adult AT2 cells leads to accelerated AT1 differentiation after acute lung injury. Single cell transcriptome analysis of lineage traced AT2 cells reveals the presence of a new AT2 cell state upon loss of Dot1L, and reveals that Dot1L regulates a complex gene expression network that includes critical transcription factors such as Id1 and Id2 and oxidative phosphorylation genes. Taken together, these data demonstrate that Dot1L regulates an epigenetic pathway in the lung essential for alveolar epithelial development and regeneration after acute injury. Overall design: To identify epigenetic pathways that control the AT2-AT1 regenerative response in the lung, we performed an organoid screen using a library of pharmacological epigenetic inhibitors, and identified Dot1L as a potential regulator of AT2 growth and differentiation. To explore the role of Dot1L in vivo, we genetically inactivated Dot1L during lung development, and in adult AT2 cells followed by lung acute injury treatments including flu and hyperoxia.  To further define the underlying mechanisms,  we performed  scRNA-seq and ChIP-seq analyses.