Genome-wide annotation of human Wnt target genes using CART: toward treatments of degenerative diseases
Résumé
The Wnt/beta signaling pathway has an important role in neuroprotection and bone formation. The activation of this pathway induces the accumulation of beta-catenin in the nucleus of the cell, which interacts with a TCF/LEF transcription factor to activate the expression of the so called Wnt target genes. Some proteins implied in neuroprotection such as CamK4, and other ones related to bone formation, e.g. Runx2, are Wnt targets. Modeling the stimulatory effects of the Wnt pathway on neuroprotection functions and bone formation allow us to analyze in silico the physiological responses to treatments of degenerative disorders such as Alzheimer's disease and osteoporosis. To obtain in-silico new Wnt target genes and insights about regulation, we built an statistical method based on CART. It is trained by the information about the transcription factor binding site motifs in the nearby regions of known Wnt target genes. Between the new Wnt target, we found genes that protect cells against amyloid beta toxicity: e.g. calcium/calmodulin-dependent protein kinase IV (CamK4), for which there exist strong evidences for up-regulation in response to both Wnt ligands and lithium.