AT2细胞在肺中具有肺泡干细胞活性，并能在稳态和损伤后进行自我更新和分化为AT1细胞。为了确定控制肺中AT2-AT1再生反应的表观遗传途径，我们使用了一种药理表观遗传抑制剂库进行器官样筛查。该筛查确定了DOT1L作为AT2细胞生长和分化的调节因子。Dot1l的体内失活导致肺发育过程中AT1和AT2基因表达的过早激活，并在急性肺损伤后加速AT1细胞的分化。单细胞转录组分析显示在Dot1l损失的情况下存在一种新的AT2细胞状态，其表现为氧化磷酸化基因表达增加以及关键转录和表观遗传因子表达的变化。综上所述，这些数据表明Dot1l在发育和急性损伤后再生过程中控制肺泡上皮细胞命运获取的速率。版权所有 © 2023年作者。Elsevier Inc.发表。保留所有权利。

AT2 cells harbor alveolar stem cell activity in the lung 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 regulator of AT2 cell growth and differentiation. In vivo inactivation of Dot1l leads to precocious activation of both AT1 and AT2 gene expression during lung development and accelerated AT1 cell differentiation after acute lung injury. Single-cell transcriptome analysis reveals the presence of a new AT2 cell state upon loss of Dot1l, characterized by increased expression of oxidative phosphorylation genes and changes in expression of critical transcription and epigenetic factors. Taken together, these data demonstrate that Dot1l controls the rate of alveolar epithelial cell fate acquisition during development and regeneration after acute injury.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.