Genome-wide identification of new Wnt/β-catenin target genes in the human genome using CART method
- Equal contributors
1 Laboratorio de Bioinformática y Expresión Génica, INTA, Universidad de Chile, Santiago, Chile
2 Laboratorio de Bioinformática y Matemática del Genoma, Centro de Modelamiento Matemático (UMI 2807, CNRS), Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, 8370459, Chile
3 Departamento de Ingeniería Matemática, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, 8370459, Chile
4 Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), MIFAB, Facultad de Ciencias Biológicas, Departamento de Biología Celular y Molecular, Pontificia Universidad Católica de Chile, Santiago, 8330025, Chile
BMC Genomics 2010, 11:348 doi:10.1186/1471-2164-11-348Published: 1 June 2010
The importance of in silico predictions for understanding cellular processes is now widely accepted, and a variety of algorithms useful for studying different biological features have been designed. In particular, the prediction of cis regulatory modules in non-coding human genome regions represents a major challenge for understanding gene regulation in several diseases. Recently, studies of the Wnt signaling pathway revealed a connection with neurodegenerative diseases such as Alzheimer's. In this article, we construct a classification tool that uses the transcription factor binding site motifs composition of some gene promoters to identify new Wnt/β-catenin pathway target genes potentially involved in brain diseases.
In this study, we propose 89 new Wnt/β-catenin pathway target genes predicted in silico by using a method based on multiple Classification and Regression Tree (CART) analysis. We used as decision variables the presence of transcription factor binding site motifs in the upstream region of each gene. This prediction was validated by RT-qPCR in a sample of 9 genes. As expected, LEF1, a member of the T-cell factor/lymphoid enhancer-binding factor family (TCF/LEF1), was relevant for the classification algorithm and, remarkably, other factors related directly or indirectly to the inflammatory response and amyloidogenic processes also appeared to be relevant for the classification. Among the 89 new Wnt/β-catenin pathway targets, we found a group expressed in brain tissue that could be involved in diverse responses to neurodegenerative diseases, like Alzheimer's disease (AD). These genes represent new candidates to protect cells against amyloid β toxicity, in agreement with the proposed neuroprotective role of the Wnt signaling pathway.
Our multiple CART strategy proved to be an effective tool to identify new Wnt/β-catenin pathway targets based on the study of their regulatory regions in the human genome. In particular, several of these genes represent a new group of transcriptional dependent targets of the canonical Wnt pathway. The functions of these genes indicate that they are involved in pathophysiology related to Alzheimer's disease or other brain disorders.