Recent studies have revealed a strong association between FOXE1 and susceptibility to differentiated thyroid cancer. However, the mechanisms through which FOXE1 promotes thyroid tumorigenesis remain elusive. Our recent work on the mechanisms behind telomerase reverse transcriptase (TERT) activation demonstrated that FOXE1 activates TERT in thyroid cell models by cooperating with either ETS-factor ELK1 (1) or ETV5 (2). We posited that FOXE1, in conjunction with ETS-factors, might also regulate other thyroid cancer-associated genes.
Leveraging publicly available ENCODE (https://www.encodeproject.org/) ATAC-seq data from four normal thyroid tissues (Thy), we performed a transcription factor motif enrichment analysis using MEME-ChIP. Our analysis showed that ATAC peaks (indicative of open chromatin) with predicted FOXE1 motifs were significantly enriched for both ETS and CTCF binding motifs, with 80% and 90% located within 300 bp of the FOXE1 motif, respectively. Subsequently, we employed the GREAT tool for ontological enrichment analysis. Top terms included: “increased thyroid tumour incidence” (FDR Q-value: 0.000439), covering genes like BRAF (+366 bp from transcriptional start site), PTEN (-665 and +508), and TP53 (+7, +809); and "abnormal telomere morphology" (Q-value: 0.0406), that included TERT (-21,370, -20,738, +47,906) and genes associated with the telomere-binding Shelterin complex, including POT1 (-25) and TERF1 (+53, +336). Next, focusing in on the TERT locus, we further evaluated Thy HiC data. Our results suggest that FOXA2 and ETV5, in tandem with CTCF binding, delineate topological associating domain (TAD) boundaries throughout this region and promote long-range interactions with the TERT promoter.
Our findings offer new insights into the relationship between FOXE1 and thyroid cancer and will necessitate experimental validation.