Ovol1 represses its own transcription by competing with transcription activator c-Myb and by recruiting histone deacetylase activity

Nair, Mahalakshmi; Bilanchone, Virginia; Ortt, Kori; Sinha, Satrajit; Dai, Xing

doi:10.1093/nar/gkl1141

Cited by 37 publications

(32 citation statements)

References 46 publications

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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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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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“…It does so either by competing for DNA binding with other transcription factors or by actively recruiting corepressor complexes (27). We identified four potential targets of OVOL1-mediated repression in trophoblast cells: MYC, TP63, ID1, and ASCL2.…”

Section: Discussionmentioning

confidence: 99%

“…We reasoned that the effects of OVOL1 deficiency on the expression of genes associated with syncytiotrophoblast differentiation could be explained best by (i) OVOL1 directly repressing genes that maintain the cytotrophoblast progenitor state or (ii) OVOL1 facilitating the activation of genes that promote syncytiotrophoblast formation. The first option is consistent with the recognized role of OVOL1 as a transcriptional repressor (27). Therefore, to screen for potential intermediary targets of OVOL1 involved in maintaining the progenitor status of cytotrophoblast cells, we perused our DNA microarray for known transcriptional regulators whose expression was down-regulated early during differentiation.…”

Section: Ovol1 Suppresses Factors Involved In Maintaining the Cytotromentioning

confidence: 99%

OVO-like 1 regulates progenitor cell fate in human trophoblast development

Renaud

Chakraborty

Mason

et al. 2015

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

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Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a specialized epithelium. This paradigm exists in human placenta, where cytotrophoblast cells either propagate or undergo a unique differentiation program: fusion into an overlying syncytiotrophoblast. Syncytiotrophoblast is the primary barrier regulating the exchange of nutrients and gases between maternal and fetal blood and is the principal site for synthesizing hormones vital for human pregnancy. How trophoblast cells regulate their differentiation into a syncytium is not well understood. In this study, we show that the transcription factor OVO-like 1 (OVOL1), a homolog of Drosophila ovo, regulates the transition from progenitor to differentiated trophoblast cells. OVOL1 is expressed in human placenta and was robustly induced following stimulation of trophoblast differentiation. Disruption of OVOL1 abrogated cytotrophoblast fusion and inhibited the expression of a broad set of genes required for trophoblast cell fusion and hormonogenesis. OVOL1 was required to suppress genes that maintain cytotrophoblast cells in a progenitor state, including MYC, ID1, TP63, and ASCL2, and bound specifically to regions upstream of each of these genes. Our results reveal an important function of OVOL1 as a regulator of trophoblast progenitor cell fate during human trophoblast development.epithelial barrier | placenta | trophoblast | OVO-like 1 | differentiation E pithelial cells turn over regularly and are reliant on a pool of cells that either replenish the reservoir of progenitor cells or differentiate into the specialized epithelium required for that tissue's function. An excellent paradigm of epithelial turnover exists in the human placenta, where mononuclear cytotrophoblast cells lining the inner portion of the chorionic villi comprise the progenitor cells of the placental epithelium. These cells either propagate to maintain an adequate reservoir of progenitor cells or undergo a differentiation program that results in fusion with an overlying syncytium (1). This syncytium, termed "syncytiotrophoblast," forms the principal epithelial barrier separating maternal and fetal blood. Syncytiotrophoblast plays a vital role in regulating nutrient, water, waste, and gas exchange between maternal and fetal circulations and produces various hormones vital for fetal development and the maintenance of human pregnancy (2). Because of its importance for fetal health and development, disruptions in syncytiotrophoblast formation or functionality can have devastating consequences for pregnancy (3-5).Syncytiotrophoblast has a limited lifespan and is shed into the maternal circulation throughout pregnancy (6, 7). Therefore, to maintain the integrity of the maternal-fetal exchange surface, syncytiotrophoblast is continually replenished by select populations of cytotrophoblast cells that forego self-renewal and instead fuse into the overlying syncytiotrophoblast. This feature, analogous to paradigms established in othe...

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“…Many important transcription factors involved in developmental regulation have an autoregulation mechanism, including mammalian c-Myb (36,48). The presence of a Myb2 binding site upstream of myb2 itself raises the possibility of myb2-positive autoregulation in G. lamblia.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cyst Wall Protein Promoters by Myb2 in Giardia lamblia

Su²,

Lee³

et al. 2008

Journal of Biological Chemistry

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Myb family transcription factors are important in regulating cell proliferation, differentiation, and cell cycle progression. Giardia lamblia differentiates into infectious cysts to survive outside of the host. During encystation, genes encoding cyst wall proteins (CWPs) are coordinately induced. We have identified an encystation-induced Myb2 protein, which binds to the promoter regions of the cwp genes and myb2 itself in vitro. To elucidate the role of Myb2 in G. lamblia, we tested the hypothesis that Myb2 can activate encystation-induced genes. We found that overexpression of Myb2 resulted in an increase of expression of CWP1 at both protein and mRNA levels. Interestingly, the Myb2-overexpressing trophozoites had increased capability to differentiate into cysts. In cotransfection assays, Myb2 was able to transactivate the cwp promoters and its own promoter in vivo, suggesting that its gene can be positively autoregulated. Moreover, deletion of the N-or C-terminal domain resulted in a decrease of transactivation and autoregulation function of Myb2. We also found that the promoter of a newly identified encystation-induced gene, the giardial myeloid leukemia factorlike gene, has the Myb2 binding sites and that its mRNA levels were increased by Myb2 overexpression. Chromatin immunoprecipitation assays confirmed that Myb2 was bound to the promoters with its binding sites. Transfection of the myb2 antisense construct reduced the levels of the cwp1 transcripts and cyst formation. Our results suggest that Myb2 is a potent transactivator of the cwp genes and other endogenous genes and plays an important role in G. lamblia differentiation into cysts.

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Ovol1 represses its own transcription by competing with transcription activator c-Myb and by recruiting histone deacetylase activity

Cited by 37 publications

References 46 publications

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

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

OVO-like 1 regulates progenitor cell fate in human trophoblast development

Regulation of Cyst Wall Protein Promoters by Myb2 in Giardia lamblia

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