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ERK3 is essential for establishment of epithelial architecture [ERK3 KD vs. TFAP2A KD]

ABSTRACT: Establishment and maintenance of epithelial architecture are essential for embryonic development and adult physiology. Here, we show that ERK3, a poorly characterized atypical MAPK, regulates epithelial architecture in vertebrates. In Xenopus embryonic epidermal epithelia, ERK3 knockdown impairs adherens and tight junction protein distribution, as well as tight junction barrier function, resulting in epidermal breakdown. Moreover, in human breast epithelial cancer cells, inhibition of ERK3 expression induces thickened epithelia with aberrant adherens and tight junctions. Microarray results suggest an involvement of TFAP2A, a transcription factor important for epithelial gene expression, in ERK3-dependent gene expression changes. TFAP2A knockdown phenocopies ERK3 knockdown in both Xenopus embryos and human cells, and ERK3 is required for full activation of TFAP2A-dependent transcription. Our findings thus reveal that ERK3 regulates epithelial architecture, possibly in cooperation with TFAP2A. We used microarrays to compare the changes in ERK3-dependent gene expression profiles with those in TFAP2A-dependent gene expression profiles in Xenopus laevis embryos.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE110428 | GEO | 2018/06/13

REPOSITORIES: GEO

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Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.

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ERK3 is essential for establishment of epithelial architecture [ERK3 KD vs. TFAP2A KD]

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