Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Dev Biol. 2019 Oct 15;454(2):108-117. doi: 10.1016/j.ydbio.2019.06.019. Epub 2019 Jun 23.
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 epithelial polarity and proximal endodermal cell differentiation, and an expansion of the distal endoderm compartment. Dnmt1 deficiency also disrupts epithelial-mesenchymal crosstalk and 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.
肺内胚层发育是通过一系列精细协调的转录过程进行的，这些过程受表观遗传机制的调节。然而，DNA 甲基化在调节肺内胚层发育中的作用仍知之甚少。我们证明，DNA 甲基转移酶 1（Dnmt1）对于肺的早期分支形态发生和抑制上皮命运特化是必需的。Dnmt1 的缺失导致早期分支缺陷、上皮极性丧失和近端内胚层细胞分化以及远端内胚层区室的扩张。Dnmt1 缺陷还破坏了上皮-间充质的相互作用，并导致远端内胚层细胞过早分化，出现肺泡 2 型细胞受限基因的过早表达。这些数据揭示了 Dnmt1 介导的 DNA 甲基化在早期肺发育中促进适当的分支形态发生、维持近端内胚层细胞命运和抑制远端上皮命运过早激活的重要性。
