The Transcription Factors Grainyhead-like 2 and NK2-Homeobox 1 Form a Regulatory Loop That Coordinates Lung Epithelial Cell Morphogenesis and Differentiation

Varma, Saaket; Cao, Yuxia; Tagne, Jean-Bosco; Lakshminarayanan, Meenakshi; Li, Jun; Friedman, Thomas B.; Morell, Robert J.; Warburton, David; Kotton, Darrell N.; Ramirez, María I.

doi:10.1074/jbc.m112.408401

Cited by 66 publications

(85 citation statements)

References 62 publications

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“…Recent analysis of Grhl2 mutants, which die around embryonic day 11.5 from neural tube closure defects, indicates that the gene plays a role in lung branching morphogenesis (17). In addition, recent studies with mouse lung alveolar-like cell lines in culture strongly support a role for Grhl2 in cell adhesion, motility, and junction formation and identify a number of likely primary targets (16). However, there has been no systematic study of GRHL proteins in primary human bronchial epithelial (HBE) cells or genomewide analysis of their potential regulatory sites.…”

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confidence: 98%

“…These are known to control many aspects of epithelial behavior, including cell polarity, motility, morphogenesis, transcellular transport, lipid metabolism, differentiation, and wound healing in multiple tissues and species from Drosophila to human (9)(10)(11)(12)(13)(14). In the embryonic mouse lung, Grhl1-3 genes exhibit differential spatiotemporal patterns of expression in the epithelium (15,16). Recent analysis of Grhl2 mutants, which die around embryonic day 11.5 from neural tube closure defects, indicates that the gene plays a role in lung branching morphogenesis (17).…”

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confidence: 99%

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Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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.

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mentioning

confidence: 98%

mentioning

confidence: 99%

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Gao

Vockley

Pauli

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Grhl2 and its paralog Grhl3 play essential roles in neural tube closure in mice (Rifat et al, 2010;Werth et al, 2010;Brouns et al, 2011;Pyrgaki et al, 2011). All three members regulate the expression of epithelial junctional genes (Yu et al, 2006;Wilanowski et al, 2008;Werth et al, 2010;Pyrgaki et al, 2011;Senga et al, 2012;Varma et al, 2012). We now report that Grhl2 controls a target gene set in placental trophoblasts and is thereby crucial to placental morphogenesis.…”

Section: Introductionmentioning

confidence: 84%

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

et al. 2015

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Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction

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“…Among these core target genes, we found previously reported targets, Cdh1 and Rab25, 8,12 and additional novel targets, including the gene encoding the zinc finger transcription factor Ovol2. Claudin 4 is a known GRHL2 target gene, 8,22 but was not represented within the core target gene set due to a lack of a differential H3K4me3 peak, although all other criteria were fulfilled. However, visual inspection indicated a reduced H3K4 trimethylation level at the Cldn4 locus in Grhl2-KD cells compared with Grhl2-Con, which did not fulfill our strict statistical criteria ( Figure 3C).…”

Section: The Core Target Gene Set Of Grhl2 Includes the Gene Encodingmentioning

confidence: 99%

A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion

Aue

Hinze

Walentin

et al. 2015

Journal of the American Society of Nephrology

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Grainyhead transcription factors control epithelial barriers, tissue morphogenesis, and differentiation, but their role in the kidney is poorly understood. Here, we report that nephric duct, ureteric bud, and collecting duct epithelia express high levels of grainyhead-like homolog 2 (Grhl2) and that nephric duct lumen expansion is defective in Grhl2-deficient mice. In collecting duct epithelial cells, Grhl2 inactivation impaired epithelial barrier formation and inhibited lumen expansion. Molecular analyses showed that GRHL2 acts as a transcriptional activator and strongly associates with histone H3 lysine 4 trimethylation. Integrating genome-wide GRHL2 binding as well as H3 lysine 4 trimethylation chromatin immunoprecipitation sequencing and gene expression data allowed us to derive a high-confidence GRHL2 target set. GRHL2 transactivated a group of genes including Ovol2, encoding the ovo-like 2 zinc finger transcription factor, as well as E-cadherin, claudin 4 (Cldn4), and the small GTPase Rab25. Ovol2 induction alone was sufficient to bypass the requirement of Grhl2 for E-cadherin, Cldn4, and Rab25 expression. Re-expression of either Ovol2 or a combination of Cldn4 and Rab25 was sufficient to rescue lumen expansion and barrier formation in Grhl2-deficient collecting duct cells. Hence, we identified a Grhl2/Ovol2 network controlling Cldn4 and Rab25 expression that facilitates lumen expansion and barrier formation in subtypes of renal epithelia. The renal collecting duct's vital electrolyte and waterregulatory functions are carried out by highly specialized cell populations. 1 The collecting duct itself is composed of a tight epithelium, which separates the urinary compartment from a hypertonic interstitium and maintains a barrier to concentration gradients. The collecting duct derives from the ureteric bud, which emanates from the nephric duct and then undergoes branching morphogenesis in response to signals from the adjacent metanephric mesenchyme. 2 Many of the genes that are critical for aspects of nephric duct development continue to be expressed in the ureteric bud and collecting duct, serving roles in development, differentiation, and maintenance of these cells (e.g., Pax2/8, Gata3, Emx2, and Hnf1b). 3 Little is known about the molecular pathways governing the specific epithelial properties of these cells, although it is clear that these epithelia share several cell biologic properties such as a uniform tubular appearance characterized by a cuboidal epithelium surrounding a fluid-filled lumen and a molecular composition of the apical junctional complex that includes

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The Transcription Factors Grainyhead-like 2 and NK2-Homeobox 1 Form a Regulatory Loop That Coordinates Lung Epithelial Cell Morphogenesis and Differentiation

Cited by 66 publications

References 62 publications

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion

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