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Mango, Susan

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Mango

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Susan

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Mango, Susan
Author's Publications: search.filters.isAuthorOfPublication.218af867-3ec9-4a5e-8a8f-ea2c912aea3d

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Now showing 1 - 7 of 7
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    Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6
    (The American Society for Cell Biology, 2017) Von Stetina, Stephen E.; Liang, Jennifer; Marnellos, Georgios; Mango, Susan
    To establish the animal body plan, embryos link the external epidermis to the internal digestive tract. In Caenorhabditis elegans, this linkage is achieved by the arcade cells, which form an epithelial bridge between the foregut and epidermis, but little is known about how development of these three epithelia is coordinated temporally. The arcade cell epithelium is generated after the epidermis and digestive tract epithelia have matured, ensuring that both organs can withstand the mechanical stress of embryo elongation; mistiming of epithelium formation leads to defects in morphogenesis. Using a combination of genetic, bioinformatic, and imaging approaches, we find that temporal regulation of the arcade cell epithelium is mediated by the pioneer transcription factor and master regulator PHA-4/FoxA, followed by the cytoskeletal regulator and kinesin ZEN-4/MKLP1 and the polarity protein PAR-6. We show that PHA-4 directly activates mRNA expression of a broad cohort of epithelial genes, including junctional factor dlg-1. Accumulation of DLG-1 protein is delayed by ZEN-4, acting in concert with its binding partner CYK-4/MgcRacGAP. Our structure–function analysis suggests that nuclear and kinesin functions are dispensable, whereas binding to CYK-4 is essential, for ZEN-4 function in polarity. Finally, PAR-6 is necessary to localize polarity proteins such as DLG-1 within adherens junctions and at the apical surface, thereby generating arcade cell polarity. Our results reveal that the timing of a landmark event during embryonic morphogenesis is mediated by the concerted action of four proteins that delay the formation of an epithelial bridge until the appropriate time. In addition, we find that mammalian FoxA associates with many epithelial genes, suggesting that direct regulation of epithelial identity may be a conserved feature of FoxA factors and a contributor to FoxA function in development and cancer.
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    Dynamic Chromatin Organization during Foregut Development Mediated by the Organ Selector Gene PHA-4/FoxA
    (Public Library of Science (PLoS), 2010) Fakhouri, Tala H. I.; Stevenson, Jeff; Chisholm, Andrew D.; Mango, Susan
    Central regulators of cell fate, or selector genes, establish the identity of cells by direct regulation of large cohorts of genes. In Caenorhabditis elegans, foregut (or pharynx) identity relies on the FoxA transcription factor PHA-4, which activates different sets of target genes at various times and in diverse cellular environments. An outstanding question is how PHA-4 distinguishes between target genes for appropriate transcriptional control. We have used the Nuclear Spot Assay and GFP reporters to examine PHA-4 interactions with target promoters in living embryos and with single cell resolution. While PHA-4 was found throughout the digestive tract, binding and activation of pharyngeally expressed promoters was restricted to a subset of pharyngeal cells and excluded from the intestine. An RNAi screen of candidate nuclear factors identified emerin (emr-1) as a negative regulator of PHA-4 binding within the pharynx, but emr-1 did not modulate PHA-4 binding in the intestine. Upon promoter association, PHA-4 induced large-scale chromatin de-compaction, which, we hypothesize, may facilitate promoter access and productive transcription. Our results reveal two tiers of PHA-4 regulation. PHA-4 binding is prohibited in intestinal cells, preventing target gene expression in that organ. PHA-4 binding within the pharynx is limited by the nuclear lamina component EMR-1/emerin. The data suggest that association of PHA-4 with its targets is a regulated step that contributes to promoter selectivity during organ formation. We speculate that global re-organization of chromatin architecture upon PHA-4 binding promotes competence of pharyngeal gene transcription and, by extension, foregut development.
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    Locking the genome: nuclear organization and cell fate
    (Elsevier BV, 2011) Meister, Peter; Mango, Susan; Gasser, Susan M
    The differentiation of pluripotent or totipotent cells into various differentiated cell types is accompanied by a restriction of gene expression patterns, alteration in histone and DNA methylation, and changes in the gross nuclear organization of eu- and heterochromatic domains. Several recent studies have coupled genome-wide mapping of histone modifications with changes in gene expression. Other studies have examined changes in the subnuclear positioning of tissue-specific genes upon transcriptional induction or repression. Here we summarize intriguing correlations of the three phenomena, which suggest that in some cases causal relationships may exist.
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    Ageing: Generations of longevity
    (Nature Publishing Group, 2011) Mango, Susan
    The lifespan of some organisms can be extended by mutations that alter how DNA is packaged in their cells. A study reveals that this effect can last for generations, even in descendants that are genetically normal.
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    Genetic Characterization of smg-8 Mutants Reveals No Role in C. elegans Nonsense Mediated Decay
    (Public Library of Science, 2012) Rosains, Jacqueline; Mango, Susan
    The nonsense mediated decay (NMD) pathway degrades mRNAs bearing premature translation termination codons. In mammals, SMG-8 has been implicated in the NMD pathway, in part by its association with SMG-1 kinase. Here we use four independent assays to show that C. elegans smg-8 is not required to degrade nonsense-containing mRNAs. We examine the genetic requirement for smg-8 to destabilize the endogenous, natural NMD targets produced by alternative splicing of rpl-7a and rpl-12. We test smg-8 for degradation of the endogenous, NMD target generated by unc-54(r293), which lacks a normal polyadenylation site. We probe the effect of smg-8 on the exogenous NMD target produced by myo-3::GFP, which carries a long 3′ untranslated region that destabilizes mRNAs. None of these known NMD targets is influenced by smg-8 mutations. In addition, smg-8 animals lack classical Smg mutant phenotypes such as a reduced brood size or abnormal vulva. We conclude that smg-8 is unlikely to encode a component critical for NMD.
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    Genome-Wide Identification of Binding Sites Defines Distinct Functions for Caenorhabditis elegans PHA-4/FOXA in Development and Environmental Response
    (Public Library of Science, 2010) Zhong, Mei; Niu, Wei; Lu, Zhi John; Sarov, Mihail; Janette, Judith; Raha, Debasish; Sheaffer, Karyn L.; Lam, Hugo Y. K.; Preston, Elicia; Slightham, Cindie; Hillier, LaDeana W.; Agarwal, Ashish; Auerbach, Raymond; Hyman, Anthony A.; Gerstein, Mark; Kim, Stuart K.; Waterston, Robert H.; Reinke, Valerie; Snyder, Michael; Murray, John I.; Mango, Susan; Brock, Trisha
    Transcription factors are key components of regulatory networks that control development, as well as the response to environmental stimuli. We have established an experimental pipeline in Caenorhabditis elegans that permits global identification of the binding sites for transcription factors using chromatin immunoprecipitation and deep sequencing. We describe and validate this strategy, and apply it to the transcription factor PHA-4, which plays critical roles in organ development and other cellular processes. We identified thousands of binding sites for PHA-4 during formation of the embryonic pharynx, and also found a role for this factor during the starvation response. Many binding sites were found to shift dramatically between embryos and starved larvae, from developmentally regulated genes to genes involved in metabolism. These results indicate distinct roles for this regulator in two different biological processes and demonstrate the versatility of transcription factors in mediating diverse biological roles.
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    The Molecular Basis of Organ Formation: Insights From the C. elegans Foregut
    (2009-11) Mango, Susan
    The digestive tracts of many animals are epithelial tubes with specialized compartments to break down food, remove wastes, combat infection and signal nutrient availability. C elegans possesses a linear, epithelial gut tube with foregut, midgut, and hindgut sections. The simple anatomy belies the developmental complexity that is involved in forming the gut from a pool of heterogeneous precursor cells. Here, I focus on the processes that specify cell fates and control morphogenesis within the embryonic foregut (pharynx) and the developmental roles of the pharynx after birth. Maternally donated factors in the pregistrula embryo converge on pha-4, a FoxA transcription factor that specifies organ identity for pharyngeal precursors. Positive feedback loops between PHA-4 and other transcription factors ensure commitment to pharyngeal fate. Binding-site affinity of PHA-4 for its target promoters contributes to the progression of the pharyngeal precursors towards differentiation. During morphogenesis, die pharyngeal precursors form an epithelial tube in a process that is independent of cadherins, catenins, and integrins but requires the kinesin zen-4/MKLP1. After birth, the pharynx and/or pha-4 are involved in repelling pathogens and controlling aging.