Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1

Wells, Julie; Lee, Briana; Cai, Anna Q.; Karapetyan, Adrine; Lee, Wan-Ju; Rugg, Elizabeth L.; Sinha, Satrajit; Nie, Qing; Dai, Xing

doi:10.1074/jbc.m109.008847

Cited by 54 publications

(47 citation statements)

References 59 publications

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“…Consistent with known Ovol1/OVOL2 regulation of Myc/MYC (Nair et al, 2006; Wells et al, 2009), Gene Set Enrichment Analysis (GSEA) (Mootha et al, 2003) of microarray data revealed an enrichment of a MYC-activated gene set (Zeller et al, 2003) in DKO cells compared to control (Figure S2A). Interestingly, DKO cells also displayed an enrichment of three “stemness” gene sets (Figure S2B).…”

Section: Resultssupporting

confidence: 71%

Transcriptional Mechanisms Link Epithelial Plasticity to Adhesion and Differentiation of Epidermal Progenitor Cells

et al. 2014

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During epithelial tissue morphogenesis, developmental progenitor cells undergo dynamic adhesive and cytoskeletal remodeling to trigger proliferation and migration. Transcriptional mechanisms that restrict such mild form of epithelial plasticity to maintain lineage-restricted differentiation in committed epithelial tissues are poorly understood. Here we report that simultaneous ablation of transcriptional repressor-encoding Ovol1 and Ovol2 results in expansion and blocked terminal differentiation of embryonic epidermal progenitor cells. Conversely, mice overexpressing Ovol2 in their skin epithelia exhibit precocious differentiation accompanied by smaller progenitor cell compartments. We show that Ovol1/2-deficient epidermal cells fail to undertake α-catenin–driven actin cytoskeletal reorganization and adhesive maturation, and exhibit changes that resemble epithelial-to-mesenchymal transition (EMT). Remarkably, these alterations as well as defective terminal differentiation are reversed upon depletion of EMT-promoting transcriptional factor Zeb1. Collectively, our findings reveal Ovol-Zeb1-α-catenin sequential repression and highlight functions of Ovol as gatekeepers of epithelial adhesion and differentiation by inhibiting progenitor-like traits and epithelial plasticity.

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Section: Resultssupporting

confidence: 71%

Transcriptional Mechanisms Link Epithelial Plasticity to Adhesion and Differentiation of Epidermal Progenitor Cells

et al. 2014

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“…Ovol2 is involved in diverse processes such as keratinocyte differentiation and cell fate decisions, as well as embryonic development. 27,39,40 Our current data reveal that most differentially regulated genes in Grhl2-deficient cells were rescued to their original expression levels, when Ovol2 was re-expressed in these cells. Furthermore, we show that Ovol2 is sufficient to functionally replace Grhl2 in lumen expansion and barrier function through induction of Cldn4 and Rab25.…”

Section: Discussionmentioning

confidence: 77%

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

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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 peaks were biased near transcriptional start sites (TSSs) of annotated genes, as more than 30% of them are located either within 1 kb upstream of the TSSs or 5′ untranslated regions (UTRs) (Figures 4A and 4B; Figures S4A and S4B). De novo motif-finding analysis identified a binding consensus CCGTTA (Figure 4C) that is identical to the in vitro Ovol1/2 binding sequence (Nair et al, 2007; Wells et al, 2009). The presence of this motif in a majority of the 5% FDR peaks (1,277 of 1,328) suggests that Ovol2 binds to the chromatin primarily through this sequence.…”

Section: Resultsmentioning

confidence: 91%

Mammary Morphogenesis and Regeneration Require the Inhibition of EMT at Terminal End Buds by Ovol2 Transcriptional Repressor

et al. 2014

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SUMMARY Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition [EMT]). However, how epithelial plasticity is kept in check in epithelial cells during tissue development and regeneration remains to be fully understood. Here we show that restricting the EMT of mammary epithelial cells by transcription factor Ovol2 is required for proper morphogenesis and regeneration. Deletion of Ovol2 blocks mammary ductal morphogenesis, depletes stem and progenitor cell reservoirs, and leads epithelial cells to undergo EMT in vivo to become nonepithelial cell types. Ovol2 directly represses myriad EMT inducers, and its absence switches response to TGF-β from growth arrest to EMT. Furthermore, forced expression of the repressor isoform of Ovol2 is able to reprogram metastatic breast cancer cells from a mesenchymal to an epithelial state. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity in development and cancer.

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Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1

Cited by 54 publications

References 59 publications

Transcriptional Mechanisms Link Epithelial Plasticity to Adhesion and Differentiation of Epidermal Progenitor Cells

Transcriptional Mechanisms Link Epithelial Plasticity to Adhesion and Differentiation of Epidermal Progenitor Cells

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

Mammary Morphogenesis and Regeneration Require the Inhibition of EMT at Terminal End Buds by Ovol2 Transcriptional Repressor

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