DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate

Lung endoderm development occurs through a series of finely coordinated transcriptional processes that are regulated by epigenetic mechanisms. However, the role of DNA methylation in regulating lung endoderm development remains poorly understood. We demonstrate that DNA methyltransferase 1 (Dnmt1) is required for early branching morphogenesis of the lungs and for restraining epithelial fate specification. Loss of Dnmt1 leads to an early branching defect, a loss of proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also leads to precocious distal endodermal cell differentiation with premature expression of alveolar type 2 cell restricted genes. These data reveal an important requirement for Dnmt1 mediated DNA methylation in early lung development to promote proper branching morphogenesis, maintain proximal endodermal cell fate, and suppress premature activation of the distal epithelial fate. Lung were harvested from E12.5 wild-type littermate and ShhCre-Dnmt1KO mice.肺内胚层发育通过一系列受表观遗传机制调控的精细协同转录过程完成。然而，DNA甲基化在调控肺内胚层发育中的作用仍有待深入阐明。本研究证实，DNA甲基转移酶1（DNA methyltransferase 1, Dnmt1）对于肺脏早期分支形态发生以及抑制上皮细胞命运特化均不可或缺。Dnmt1缺失会引发早期分支缺陷、近端内胚层细胞分化能力丧失，并导致远端内胚层区域扩张。Dnmt1缺失还会引发远端内胚层细胞早熟分化，并伴随肺泡Ⅱ型细胞（alveolar type 2 cell）特异性基因的提前表达。上述研究结果揭示，Dnmt1介导的DNA甲基化在肺脏早期发育中发挥关键作用：可促进正常分支形态发生、维持近端内胚层细胞命运，并抑制远端上皮细胞命运的提前激活。本研究从E12.5天龄的野生型同窝仔鼠以及ShhCre-Dnmt1KO小鼠体内获取肺组织。