Dnmt1 is required for proximal-distal patterning of the lung endoderm and for 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) i...

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Bibliographic Details
Published in:Developmental biology 2019-10, Vol.454 (2), p.108-117
Main Authors: Liberti, Derek C., Zepp, Jarod A., Bartoni, Christina A., Liberti, Kyle H., Zhou, Su, Lu, Minmin, Morley, Michael P., Morrisey, Edward E.
Format: Article
Language:English
Subjects:
Alveolar Epithelial Cells - metabolism
Animals
Cell Differentiation - genetics
Cell Lineage - physiology
Cell Polarity
Cell Proliferation - genetics
DNA (Cytosine-5-)-Methyltransferase 1 - genetics
DNA (Cytosine-5-)-Methyltransferase 1 - metabolism
DNA (Cytosine-5-)-Methyltransferase 1 - physiology
DNA Methylation - genetics
Endoderm - metabolism
Epigenesis, Genetic - genetics
Epithelial Cells - cytology
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Developmental
Lung - cytology
Lung - metabolism
Lung - pathology
Male
Mice
Morphogenesis
Organogenesis - physiology
Signal Transduction - physiology
Transcription Factors - metabolism
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Summary: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. •Loss of Dnmt1 leads to precocious distalization and loss of proximal endoderm.•Dnmt1 is required for branching morphogenesis and epithelial-mesenchymal crosstalk.•Epithelial shape and polarity are disrupted in Dnmt1 deficient lungs.•Dnmt1 mutants exhibit premature activation of the AT2 cell transcriptional program.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2019.06.019