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Dot1L regulates the rate of lung alveolar regeneration through control of oxidative phosphorylatio

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE210800 | GEO | 2023/10/11

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Dot1L regulates the rate of lung alveolar regeneration through control of oxidative phosphorylatio

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