Fzd2 is a Wnt receptor expressed in the embryonic lung. We made a conditional knockout of Fzd2 to specifically address the role of signaling through Fzd2 in lung epithelial development.
Wnt ligand/Frizzled 2 receptor signaling regulates tube shape and branch-point formation in the lung through control of epithelial cell shape.
Specimen part
View SamplesEzh2 epigenetically suppresses developmentally-regulated genes. Ezh2 is highly expressed during development, including in the lung. We knocked out Ezh2 in the developing lung epithelium using a Shh-cre driver which is active in foregut endoderm prior to lung morphogenesis. Many developmentally regulated genes became derepressed in the mutant lungs, leading to defects in lung development.
Ezh2 represses the basal cell lineage during lung endoderm development.
Specimen part
View SamplesTo identify potential biological functions for three lncRNAs (NANCI, LL12, and LL34) we used shRNAs to knockdown expression of lncRNAs in MLE12 cells, a cell resembling type two lung epithelial cells. This data set contains the microarrays looking at gene expression.
Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development.
Treatment
View SamplesThe molecular mechanism of how lung sacculation occurs is poorly understood. Loss of epithelial Hdac3 results in defects in the proper expansion of distal lung saccules into primitive alveoli. In this microarray, we seek to investigate the gene profile changes caused by loss of Hdac3 to better understand the molecular pathways that are regulated by Hdac3 during lung sacculation.
HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation.
Specimen part
View SamplesAlthough mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcomes amongst lung cancer patients suggesting the importance of other pathways. Wnt/-catenin signaling is a known oncogenic pathway that plays a well defined role in colon and skin cancer but its role in lung cancer remains unclear. We show that activation of Wnt/-catenin in the bronchiolar epithelium of the adult lung does not promote tumor development by itself. However, activation of Wnt/- catenin signaling leads to a dramatic increase in tumor formation both in overall tumor number and size compared to KrasG12D alone. We show that activation of Wnt/- catenin signaling significantly alters the KrasG12D tumor phenotype resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This is associated with a decrease in E- cadherin expression at the cell surface which may increase metastasis in Wnt/-catenin signaling positive tumors. Together, these data suggest that activation of Wnt/-catenin signaling in combination with other oncogenic pathways in lung epithelium may lead to a more aggressive phenotype due to the imposition of an embryonic distal progenitor phenotype accompanied by decreased E-cadherin expression.
Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.
Sex, Age, Specimen part
View SamplesFoxp1/4 transcription factors are conserved transcriptional repressors expressed in overlapping patterns during lung development as well as in the adult lung. However, the role of Foxp1/4 in development and homeostasis of the pseudostratified epithelium of the proximal airways and trachea is unknown.
Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2.
Specimen part
View SamplesThe purpose of this study was to identify gene expression changes associated with congenital lung malformations.
Novel Molecular and Phenotypic Insights into Congenital Lung Malformations.
Sex, Age, Specimen part, Subject
View SamplesThe lung alveolus is the primary site of gas exchange in mammals. Within the alveolus, the alveolar type 2 (AT2) epithelial cell population generates surfactant to maintain alveolar structure and harbors a regenerative capacity to repair the alveolus after injury. We show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the AT2 cell population is critical for regenerating the alveolar niche. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a majority of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome, and functional phenotype with specific responsiveness to Wnt and FGF signaling that modulates differentiation and self-renewal, respectively. Importantly, human AEPs (hAEPs) can be isolated and characterized through a conserved surface marker and are required for human alveolar self-renewal and differentiation using alveolar organoid assays. Together, our findings show that AEPs are an evolutionarily conserved alveolar progenitor lineage essential for regenerating the alveolar niche in the mammalian lung. Overall design: Examination of open chromatin in 2 subtypes of alveolar epithelial cell populations
Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor.
Sex, Age, Specimen part, Race, Subject
View SamplesBRD4 is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass (ICM), which gives rise to embryonic stem cells (ESCs). We investigated the functions of Brd4 in the ESCs in the present study.
BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos.
Specimen part
View SamplesLeft ventricular myocardium was snap-frozen at time of cardiac transplantation from patients with advanced idiopathic or ischemic cardiomyopathy, or at time of harvest from unused donor heart that serve as a nonfailing control. No subjects received mechanical support devices.
Transcriptional genomics associates FOX transcription factors with human heart failure.
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