The canonical Wnt pathway plays a central role in stem cell maintenance, differentiation and proliferation in the adult, self-renewing intestinal epithelium. Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding TCF factors and the transcriptional co-activator β-catenin. Constitutive, aberrant transcriptional activity of the TCF4/β-catenin complex, caused by mutations in APC, AXIN or β-catenin, is the primary transforming factor in colorectal cancer. At present, despite great inroads into the processes involved in Wnt-dependent transcriptional regulation, the mechanisms by which TCF4/β-catenin regulate target genes remain incompletely understood. My post-doctoral research on these mechanisms uncovered tantalizing clues for the existence of previously unappreciated layers in the Wnt-dependent repertoire of transcriptional targets and mediators. These clues point to the existence of long intergenic non-coding RNAs (lincRNAs), the expression of which is regulated by the Wnt pathway and which, in turn, mediate its transcriptional activity and output. The proposed work aims at i) the systematic identification of such Wnt-regulated lincRNAs ii) the discovery of the protein factors with which they interact and iii) the elucidation of their functional and mechanistic contribution to Wnt-dependent transcription. These studies promise to shed light on new players and principles involved in normal and abnormal intestine physiology and to generate novel therapeutic targets in colorectal cancer.
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