Multi-omics analyses integration reveals a novel TRF2-miR-181a-5p-S100A10 regulatory axis in colon cancer [RNA-seq]

The Telomeric repeat-binding factor 2 (TRF2) binds to TTAGGG repeats located at chromosomes ends and ensures telomere protection together with the other members of shelterin. In addition to its well-known role in telomere maintenance, TRF2 can also bind to interstitial telomeric sequences (ITS) and regulate the expression of specific genes with a consequent impact on tumor formation and progression. However, a comprehensive analysis of the impact of TRF2 on global gene expression of human cancer cells is still missing and underlying mechanisms of TRF2-mediated gene expression regulation remain to be further elucidated. Here, by performing RNA sequencing analysis, we found that TRF2 alters the expression of 717 genes involved in various cancer-related pathways. Unexpectedly, Chromatin immunoprecipitation sequencing analysis revealed, that just a small portion of Differentially Regulated genes (DEGs) are directly bound by TRF2, suggesting the existence of alternative mechanisms of TRF2-mediated gene regulation. In particular, we found that TRF2 binds to various non-coding RNA (ncRNAs) regions, including miRNA host genes. Moreover, interactomic analysis unveiled that RNA binding proteins are well represented among TRF2 interactors, supporting the involvement of TRF2 in ncRNAs-mediated mechanisms. Through the intersection of omics-analyses, we provided here experimental evidence of a multilayered mechanism of regulation where TRF2, interacting with TATA-box binding protein associated factor 15 (TAF15), regulates miR181A1 host gene and mature miR-181a-5p expression, which in turn targets S100A10, a known plasma membrane with oncogenic role. Our work shows, for the first time, a broad overview on the extratelomeric role of TRF2 in human cancer revealing, at the same time, a new axis through which TRF2 contributes to cancer progression.