DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129177 | GEO | 2020/01/24
REPOSITORIES: GEO
Similar Datasets
Project description:The lung is a branched tubular network with two distinct compartments — the proximal conducting airways and the peripheral gas exchange region — separated by a discrete boundary termed the bronchoalveolar duct junction (BADJ). Here we image the developing mouse lung in three-dimensions and show that two nested developmental waves demarcate the BADJ under the control of a global hormonal signal. A first wave of branching morphogenesis progresses throughout embryonic development, generating branches for both compartments. A second wave of conducting airway differentiation follows the first wave but terminates earlier, specifying the proximal compartment and setting the BADJ. The second wave is terminated by a glucocorticoid signaling: premature activation or loss of glucocorticoid signaling causes a proximal or distal shift, respectively, in BADJ location. The results demonstrate a novel mechanism of boundary formation in complex, three-dimensional organs and provide new insights into glucocorticoid therapies for lung defects in premature birth. RNAs were extracted from E14 lungs cultured in control and dexamethasone media for 24 hours using Trizol reagents and Qiagen RNeasy Micro kit. Two control and two treated samples were analyzed.
2014-05-22 | E-GEOD-56831 | biostudies-arrayexpress
Project description:During the step-wise specification and differentiation of tissue specific multipotent progenitor cells, lineage-specific transcriptional networks are either activated or repressed to orchestrate progenitor cell commitment. The gas exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and type 2 (AT2) cells, and the timing of lineage commitment of these cells is critical for correct formation of this niche and postnatal survival. To define the ontogeny of alveolar cell fate in the lung, we used lineage tracing studies combined with spatially specific mRNA transcript and protein expression combined with single cell RNA-seq analysis. These studies reveal that commitment to alveolar epithelial cell fate occurs far earlier than previously appreciated, concomitant with the proximal-distal specification of epithelial progenitors and branching morphogenesis. Using a novel dual lineage tracing system, we show that a small population of alveolar cells express markers of both AT1 and AT2 cells, whose fate is ultimately restricted to a single lineage. However, these bi-transcriptional cells generate only a minor portion of the mature alveolar epithelium. These data reveal a new paradigm of organ formation where early lineage commitment occurs during the nascent stages of development coincident with broad tissue patterning processes including axial patterning of the endoderm and branching morphogenesis.
2019-02-08 | GSE113320 | GEO
Project description:The lung is a branched tubular network with two distinct compartments — the proximal conducting airways and the peripheral gas exchange region — separated by a discrete boundary termed the bronchoalveolar duct junction (BADJ). Here we image the developing mouse lung in three-dimensions and show that two nested developmental waves demarcate the BADJ under the control of a global hormonal signal. A first wave of branching morphogenesis progresses throughout embryonic development, generating branches for both compartments. A second wave of conducting airway differentiation follows the first wave but terminates earlier, specifying the proximal compartment and setting the BADJ. The second wave is terminated by a glucocorticoid signaling: premature activation or loss of glucocorticoid signaling causes a proximal or distal shift, respectively, in BADJ location. The results demonstrate a novel mechanism of boundary formation in complex, three-dimensional organs and provide new insights into glucocorticoid therapies for lung defects in premature birth.
2014-05-22 | GSE56831 | GEO
Project description:DNMT1 is required for proximal-distal patterning of the lung endoderm and restraining alveolar type 2 cell fate
| PRJNA530392 | ENA
Project description:To study gene expression during endodermal organogenesis, we sought to identify genes expressed in restricted domains during organogenesis. For gene expression analysis, six morphologically distinct endodermal domains were dissected at E11.5: the esophageal region; the lung and distal tracheal region; the stomach region; the hepatic region; the dorsal and ventral pancreatic region; and the intestinal region. Through flow cytometric separation using EpCAM expression to distinguish endoderm from surrounding mesenchyme, pure populations of endoderm progenitors from the esophageal, lung, stomach, pancreatic, and intestinal regions were isolated. Expression of Liv2 was used to isolate a pure population of hepatic endoderm progenitors. Keywords: cell type comparison Three biological replicates each containing dissected organ domains from 10-12 pooled embryos flow cytometrically sorted to isolate endoderm were amplified using Ambion Illumina TotalPrep RNA Amplification kit and arrayed on Illumina MouseRef8 v2 chips
2010-06-24 | E-GEOD-13040 | biostudies-arrayexpress
Project description:During development, the proximal and distal regions of respiratory tract undergo distinct processes that ultimately give rise to conducting airways and alveoli. To gain insights into the genetic pathways differentially activated in these regions when branching morphogenesis is initiating, we characterized their transcriptional profiles in murine rudiments isolated at embryonic day 11.5.
2007-09-29 | E-GEOD-1423 | biostudies-arrayexpress
Project description:To study gene expression during endodermal organogenesis, we sought to identify genes expressed in restricted domains during organogenesis. For gene expression analysis, six morphologically distinct endodermal domains were dissected at E11.5: the esophageal region; the lung and distal tracheal region; the stomach region; the hepatic region; the dorsal and ventral pancreatic region; and the intestinal region. Through flow cytometric separation using EpCAM expression to distinguish endoderm from surrounding mesenchyme, pure populations of endoderm progenitors from the esophageal, lung, stomach, pancreatic, and intestinal regions were isolated. Expression of Liv2 was used to isolate a pure population of hepatic endoderm progenitors. Keywords: cell type comparison
2008-12-30 | GSE13040 | GEO
Project description:Background DNA methylation is an epigenetic mark that restricts chromatin accessibility and serves to modulate temporal and spatial gene expression during organogenesis. Dnmt1 is one of the most studied DNA methyltransferases, and it is primarily involved in preserving the DNA methylation pattern in cells undergoing mitotic division. While the role of Dnmt1 in the embryonic lung endoderm has been revealed, its role in expansion, maintence and differentiation of the embryonic lung mesoderm is mostly unknown. Here, we present the first evidence showing that Dnmt1 is necessary for the proper development of the embryonic lung mesoderm. By selectively deleting Dnmt1 in the embryonic lung mesoderm we found that Dnmt1 is critical for the development of embryonic vasculature and fully commitment of mesoderm towards the lung mesenchymal cell lineages. Results Dnmt1 deletion in the embryonic lung mesenchyme at the E7.5 stage led to a lethal phenotype which was characterized by bilateral lung hypoplasia, impaired lung branching morphogenesis, and widespread hemorrhages in the parenchyma. The genesis of the hemorrhages was likely a result of halted development of lung vasculature, specifically the ontogeny of pericytes, which was detected in the mutant lungs. However, despite the severe mesenchyme alteration, differentiation of the lung endoderm appeared normal. When Dnmt1 was deleted at later developmental periods (E13.5), the lung matured normally and mutant pups were viable, although reduced differentiation of Pdgfr- myofibroblasts and alveolar simplification were observed in all mutant animals as soon as 7 days after birth. Gene expression profiling studies revealed that deletion of Dnmt1 induced the ectopic expression of genes specific for testis, placenta, and ovary, such as Tex10.1, Tex19.1 and Pet2 which suggested a loss of commitment of the lung mesoderm toward the pulmonary cell lineages. Conclusions Taken together our findings have shown that dnmt1 expression in the mesenchyme of the developing lung is crucial for restricting the differentiation capacity of the pulmonary mesoderm and, thus, ensuring the adequate differentiation of vasculature cells and myofibroblasts in the fetal and postnatal lung.
2021-06-15 | GSE175640 | GEO
Project description:Background DNA methylation is an epigenetic mark that restricts chromatin accessibility and serves to modulate temporal and spatial gene expression during organogenesis. Dnmt1 is one of the most studied DNA methyltransferases, and it is primarily involved in preserving the DNA methylation pattern in cells undergoing mitotic division. While the role of Dnmt1 in the embryonic lung endoderm has been revealed, its role in expansion, maintence and differentiation of the embryonic lung mesoderm is mostly unknown. Here, we present the first evidence showing that Dnmt1 is necessary for the proper development of the embryonic lung mesoderm. By selectively deleting Dnmt1 in the embryonic lung mesoderm we found that Dnmt1 is critical for the development of embryonic vasculature and fully commitment of mesoderm towards the lung mesenchymal cell lineages. Results Dnmt1 deletion in the embryonic lung mesenchyme at the E7.5 stage led to a lethal phenotype which was characterized by bilateral lung hypoplasia, impaired lung branching morphogenesis, and widespread hemorrhages in the parenchyma. The genesis of the hemorrhages was likely a result of halted development of lung vasculature, specifically the ontogeny of pericytes, which was detected in the mutant lungs. However, despite the severe mesenchyme alteration, differentiation of the lung endoderm appeared normal. When Dnmt1 was deleted at later developmental periods (E13.5), the lung matured normally and mutant pups were viable, although reduced differentiation of Pdgfr- myofibroblasts and alveolar simplification were observed in all mutant animals as soon as 7 days after birth. Gene expression profiling studies revealed that deletion of Dnmt1 induced the ectopic expression of genes specific for testis, placenta, and ovary, such as Tex10.1, Tex19.1 and Pet2 which suggested a loss of commitment of the lung mesoderm toward the pulmonary cell lineages. Conclusions Taken together our findings have shown that dnmt1 expression in the mesenchyme of the developing lung is crucial for restricting the differentiation capacity of the pulmonary mesoderm and, thus, ensuring the adequate differentiation of vasculature cells and myofibroblasts in the fetal and postnatal lung.
2021-06-15 | GSE174747 | GEO
Project description:Background DNA methylation is an epigenetic mark that restricts chromatin accessibility and serves to modulate temporal and spatial gene expression during organogenesis. Dnmt1 is one of the most studied DNA methyltransferases, and it is primarily involved in preserving the DNA methylation pattern in cells undergoing mitotic division. While the role of Dnmt1 in the embryonic lung endoderm has been revealed, its role in expansion, maintence and differentiation of the embryonic lung mesoderm is mostly unknown. Here, we present the first evidence showing that Dnmt1 is necessary for the proper development of the embryonic lung mesoderm. By selectively deleting Dnmt1 in the embryonic lung mesoderm we found that Dnmt1 is critical for the development of embryonic vasculature and fully commitment of mesoderm towards the lung mesenchymal cell lineages. Results Dnmt1 deletion in the embryonic lung mesenchyme at the E7.5 stage led to a lethal phenotype which was characterized by bilateral lung hypoplasia, impaired lung branching morphogenesis, and widespread hemorrhages in the parenchyma. The genesis of the hemorrhages was likely a result of halted development of lung vasculature, specifically the ontogeny of pericytes, which was detected in the mutant lungs. However, despite the severe mesenchyme alteration, differentiation of the lung endoderm appeared normal. When Dnmt1 was deleted at later developmental periods (E13.5), the lung matured normally and mutant pups were viable, although reduced differentiation of Pdgfr- myofibroblasts and alveolar simplification were observed in all mutant animals as soon as 7 days after birth. Gene expression profiling studies revealed that deletion of Dnmt1 induced the ectopic expression of genes specific for testis, placenta, and ovary, such as Tex10.1, Tex19.1 and Pet2 which suggested a loss of commitment of the lung mesoderm toward the pulmonary cell lineages. Conclusions Taken together our findings have shown that dnmt1 expression in the mesenchyme of the developing lung is crucial for restricting the differentiation capacity of the pulmonary mesoderm and, thus, ensuring the adequate differentiation of vasculature cells and myofibroblasts in the fetal and postnatal lung.
2021-06-15 | GSE174610 | GEO