Tissue and cancer-specific expression of DIEXF is epigenetically mediated by an Alu repeat

Alu repeats constitute a major fraction of human genome and for a small subset of them a role in gene regulation has been described. The number of studies focused on the functional characterization of particular Alu elements is very limited. Most Alu elements are DNA methylated and then assumed to lie in repressed chromatin domains. We hypothesize that Alu elements with low or variable DNA methylation are candidates for a functional role. In a genome-wide study in normal and cancer tissues, we pinpointed an Alu repeat (AluSq2) with differential methylation located upstream of the promoter region of the <i>DIEXF</i> gene. <i>DIEXF</i> encodes a highly conserved factor essential for the development of zebrafish digestive tract. To characterize the contribution of the Alu element to the regulation of <i>DIEXF</i> we analysed the epigenetic landscapes of the gene promoter and flanking regions in different cell types and cancers. Alternate epigenetic profiles (DNA methylation and histone modifications) of the AluSq2 element were associated with <i>DIEXF</i> transcript diversity as well as protein levels, while the epigenetic profile of the CpG island associated with the <i>DIEXF</i> promoter remained unchanged. These results suggest that AluSq2 might directly contribute to the regulation of <i>DIEXF</i> transcription and protein expression. Moreover, AluSq2 was DNA hypomethylated in different cancer types, pointing out its putative contribution to <i>DIEXF</i> alteration in cancer and its potential as tumoural biomarker.