Pantelis Hatzis Research Group

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.

We have previously identified a number of long non-coding RNAs that are regulated, either positively or negatively by the Wnt pathway, in colorectal cancer cells. One of these, which we have termed WiNTeRLiNC3, is a nuclear lncRNA negatively regulated by Wnt; its expression is significantly reduced in colorectal cancer and its overexpression in cis reduces the viability of CRC cells, by affecting cell adhesion and proliferation. It does so by affecting the expression in cis of a nearby cell adhesion-associated protein-coding gene. Ongoing experiments aim at elucidating the proteins and the mechanism involved in mediating the effects of WiNTeRLiNC3on its gene target and on cellular phenotypes.

Recent, both high-throughput, computational, and other, methodologies have aided the identification of a subset of long non-coding RNAs that have, in fact, protein-coding potential. Some of these genes have been found to indeed code for small proteins, with significant functions in various cellular compartments. Data meta-analyses coupled to experimental approaches have allowed us to identify a small number of such small-protein encoding lncRNAs. We are focusing on one of these, provisionally termed mito-SEP1, which, when overexpressed, localizes to mitochondria, negatively affecting mitochondrial potential and function. Ongoing experiments aim at elucidating its interaction partners and mode of action in mitochondria and its contribution to cellular bioenergetics.