The experiments described in this proposal will address the regulatory processes that sculpt gut organogenesis in the embryo. My lab has a longstanding interest in organogenesis of the foregut, or pharynx, with a particular focus on its transcriptional regulatory processes. C. elegans is uniquely suited for this analysis because it offers tremendous experimental advantages: transparency, single-cell resolution, genetics, rapid transgene methodology, short generation time, ease of growth for biochemistry, simple anatomy, robust RNAi and increasingly powerful genomics.
In Aim 1 we will explore PHA-4 association with its target genes to test models of cell-fate specification and to delimit regulation of PHA-4 binding in vivo. We will use Chromatin Immunoprecipitation (ChIP) and in vivo imaging to define genes bound by PHA-4 at different times and in different genetic backgrounds.
In Aim 2, we will test the hypothesis that environmental sensing by the mother is communicated to her progeny, which in turn modulates digestive tract development, growth and/or physiology. We will analyze pharyngeal development in wild-type vs. pha-4 mutants that have been compromised for chemosensation in particular cells or at specific stages. We have extensive experience with the techniques described in this proposal, and we will collaborate with experts in the field for any new technology. Given the conservation between worms and mammals, the processes we uncover will likely be relevant for understanding human organogenesis and diseases that affect organ development or function such as cancer, diabetes and metabolic syndrome.
Our goal is to understand the molecular underpinnings of organ formation, specifically the anterior gut or foregut. In the coming years we propose to analyze the role of the key regulator pha-4 for specifying foregut identity (Aim1). We will also examine the role of the parental environment for modifying gut development in the offspring (Aim 2). The molecules and pathways we uncover will have repercussions for identifying genes involved in human health and disease such as cancer, diabetes or birth defects, and will illuminate how the environment (e.g. amount or quality of food, stress, oxygen or drugs) can impact the health of subsequent generations.
|Mutlu, Beste; Chen, Huei-Mei; Moresco, James J et al. (2018) Regulated nuclear accumulation of a histone methyltransferase times the onset of heterochromatin formation in C. elegans embryos. Sci Adv 4:eaat6224|
|Von Stetina, Stephen E; Liang, Jennifer; Marnellos, Georgios et al. (2017) Temporal regulation of epithelium formation mediated by FoxA, MKLP1, MgcRacGAP, and PAR-6. Mol Biol Cell 28:2042-2065|
|Zaret, Kenneth S; Mango, Susan E (2016) Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr Opin Genet Dev 37:76-81|
|Hsu, H-T; Chen, H-M; Yang, Z et al. (2015) TRANSCRIPTION. Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4. Science 348:1372-6|
|Von Stetina, Stephen E; Mango, Susan E (2015) PAR-6, but not E-cadherin and ?-integrin, is necessary for epithelial polarization in C. elegans. Dev Biol 403:5-14|
|Choi, Youngeun; Mango, Susan E (2014) Hunting for Darwin's gemmules and Lamarck's fluid: transgenerational signaling and histone methylation. Biochim Biophys Acta 1839:1440-53|
|Rosains, Jacqueline; Mango, Susan E (2012) Genetic characterization of smg-8 mutants reveals no role in C. elegans nonsense mediated decay. PLoS One 7:e49490|
|Mango, Susan E (2011) Ageing: generations of longevity. Nature 479:302-3|
|Meister, Peter; Mango, Susan E; Gasser, Susan M (2011) Locking the genome: nuclear organization and cell fate. Curr Opin Genet Dev 21:167-74|