Context-dependent transcription factors play a critical role in defining which genes are regulated during development and disease, allowing the same factors to play different roles in different cells. The C. elegans embryo is an deal system for a comprehensive study of the role of lineage history in the context-dependent regulation of cell fate because of its invariant lineage and powerful experimental tools. We recently developed automated lineage tracing and expression mapping methods for C. elegans embryogenesis and measured the expression of over 127 fluorescent reporters for transcription factor (TF) expression in every cell of developing embryos. From this dataset, we identified over 30 TFs whose expression correlates directly with both lineage identity and Wnt signaling but not with terminal fate.
In Aim 1, we will apply our lineage tracing methods to elucidate how context factors determine differential cellular respones to Wnt signaling, a key cell fate regulator and driver of oncogenesis. We will do this by assaying binding of the Wnt effector POP-1 to candidate targets, genome-wide mapping of POP-1 binding and detailed cis-regulatory analysis.
In Aim 2, we will determine the function of TFs with lineage-specific expression by high-resolution phenotyping and genome-wide expression profiling of mutants. These studies will define mechanisms by which lineage identity is translated into cell fate and shed light on context-dependent differences in TF and Wnt targets in C. elegans and other organisms.
In animal development the single-celled zygote divides, and its progeny differentiate to produce an incredible diversity of terminally differentiated cell type. This process is regulated in large part by conserved regulatory processes including transcription factors and signaling pathways whose function is conserved from humans to invertebrates. This project will identify mechanisms used by one of these conserved regulatory processes, the Wnt signaling pathway, to regulate different genes in different cells. This context-dependent regulation of gene expression by Wnt is likely a major factor in the prominent role of Wnt in cancer. We will also define in detail the role of five highly conserved transcription factors in ealy embryonic development. We will study these processes in the C. elegans embryo, whose stereotyped development and powerful experimental tools facilitate rapid discovery of new mechanisms that are likely to be relevant to human health and disease.
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|Zacharias, Amanda L; Murray, John Isaac (2016) Combinatorial decoding of the invariant C. elegans embryonic lineage in space and time. Genesis 54:182-97|
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|Walton, Travis; Preston, Elicia; Nair, Gautham et al. (2015) The Bicoid class homeodomain factors ceh-36/OTX and unc-30/PITX cooperate in C. elegans embryonic progenitor cells to regulate robust development. PLoS Genet 11:e1005003|