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- All Subjects: Neural Development
- All Subjects: Pan-cancer
- Creators: Plaisier, Christopher
Description
The WNT signaling pathway plays numerous roles in development and maintenance of adult homeostasis. In concordance with it’s numerous roles, dysfunction of WNT signaling leads to a variety of human diseases ranging from developmental disorders to cancer. WNT signaling is composed of a family of 19 WNT soluble secreted glycoproteins, which are evolutionarily conserved across all phyla of the animal kingdom. WNT ligands interact most commonly with a family of receptors known as frizzled (FZ) receptors, composed of 10 independent genes. Specific interactions between WNT proteins and FZ receptors are not well characterized and are known to be promiscuous, Traditionally canonical WNT signaling is described as a binary system in which WNT signaling is either off or on. In the ‘off’ state, in the absence of a WNT ligand, cytoplasmic β-catenin is continuously degraded by the action of the APC/Axin/GSK-3β destruction complex. In the ‘on’ state, when WNT binds to its Frizzled (Fz) receptor and LRP coreceptor, this protein destruction complex is disrupted, allowing β-catenin to translocate into the nucleus where it interacts with the DNA-bound T cell factor/lymphoid factor (TCF/LEF) family of proteins to regulate target gene expression. However in a variety of systems in development and disease canonical WNT signaling acts in a gradient fashion, suggesting more complex regulation of β-catenin transcriptional activity. As such, the traditional ‘binary’ view of WNT signaling does not clearly explain how this graded signal is transmitted intracellularly to control concentration-dependent changes in gene expression and cell identity. I have developed an in vitro human pluripotent stem cell (hPSC)-based model that recapitulates the same in vivo developmental effects of the WNT signaling gradient on the anterior-posterior (A/P) patterning of the neural tube observed during early development. Using RNA-seq and ChIP-seq I have characterized β-catenin binding at different levels of WNT signaling and identified different classes of β-catenin peaks that bind cis-regulatory elements to influence neural cell fate. This work expands the traditional binary view of canonical WNT signaling and illuminates WNT/β-catenin activity in other developmental and diseased contexts.
ContributorsCutts, Joshua Patrick (Author) / Brafman, David A (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Nikkhah, Mehdi (Committee member) / Wang, Xiao (Committee member) / Plaisier, Christopher (Committee member) / Arizona State University (Publisher)
Created2019
Description
The human transcriptional regulatory machine utilizes hundreds of transcription factors which bind to specific genic sites resulting in either activation or repression of targeted genes. Networks comprised of nodes and edges can be constructed to model the relationships of regulators and their targets. Within these biological networks small enriched structural patterns containing at least three nodes can be identified as potential building blocks from which a network is organized. A first iteration computational pipeline was designed to generate a disease specific gene regulatory network for motif detection using established computational tools. The first goal was to identify motifs that can express themselves in a state that results in differential patient survival in one of the 32 different cancer types studied. This study identified issues for detecting strongly correlated motifs that also effect patient survival, yielding preliminary results for possible driving cancer etiology. Second, a comparison was performed for the topology of network motifs across multiple different data types to identify possible divergence from a conserved enrichment pattern in network perturbing diseases. The topology of enriched motifs across all the datasets converged upon a single conserved pattern reported in a previous study which did not appear to diverge dependent upon the type of disease. This report highlights possible methods to improve detection of disease driving motifs that can aid in identifying possible treatment targets in cancer. Finally, networks where only minimally perturbed, suggesting that regulatory programs were run from evolved circuits into a cancer context.
ContributorsStriker, Shawn Scott (Author) / Plaisier, Christopher (Thesis advisor) / Brafman, David (Committee member) / Wang, Xiao (Committee member) / Arizona State University (Publisher)
Created2020