Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium
Xia Gao,Christopher M. Vockley,Florencia Pauli,Kimberly M. Newberry,Yan Xue,Scott H. Randell,Timothy E. Reddy,Brigid L.M. Hogan +7 more
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TLDR
The hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility is supported.Abstract:
Most of the airways of the human lung are lined by an epithelium made up of ciliated and secretory luminal cells and undifferentiated basal progenitor cells. The integrity of this epithelium and its ability to act as a selective barrier are critical for normal lung function. In other epithelia, there is evidence that transcription factors of the evolutionarily conserved grainyheadlike (GRHL) family play key roles in coordinating multiple cellular processes required for epithelial morphogenesis, differentiation, remodeling, and repair. However, only a few target genes have been identified, and little is known about GRHL function in the adult lung. Here we focus on the role of GRHL2 in primary human bronchial epithelial cells, both as undifferentiated progenitors and as they differentiate in air–liquid interface culture into an organized mucociliary epithelium with transepithelial resistance. Using a dominant-negative protein or shRNA to inhibit GRHL2, we follow changes in epithelial phenotype and gene transcription using RNA sequencing or microarray analysis. We identify several hundreds of genes that are directly or indirectly regulated by GRHL2 in both undifferentiated cells and air–liquid interface cultures. Using ChIP sequencing to map sites of GRHL2 binding in the basal cells, we identify 7,687 potential primary targets and confirm that GRHL2 binding is strongly enriched near GRHL2-regulated genes. Taken together, the results support the hypothesis that GRHL2 plays a key role in regulating many physiological functions of human airway epithelium, including those involving cell morphogenesis, adhesion, and motility.read more
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Dynamic Changes in Intracellular ROS Levels Regulate Airway Basal Stem Cell Homeostasis through Nrf2-Dependent Notch Signaling
Manash K. Paul,Bharti Bisht,Daphne O. Darmawan,Richard Chiou,Vi Luan Ha,William D. Wallace,Andrew T. Chon,Ahmed E. Hegab,Tristan Grogan,David Elashoff,Jackelyn A. Alva-Ornelas,Brigitte N. Gomperts +11 more
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Epithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease
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Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome.
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Crumbs3-Mediated Polarity Directs Airway Epithelial Cell Fate through the Hippo Pathway Effector Yap
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TL;DR: It is demonstrated that Crb3, a Crumbs isoform that determines epithelial apical domain identity, is required for airway differentiation by controlling the localization of the transcriptional regulator Yap, and that polarity-dependent cues control airway cell differentiation.
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