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bioRxiv · 10.1101/2022.05.18.492493

The TERT promoter is polycomb-repressed in neuroblastoma cells with long telomeres

Graham, M. K.·Xu, B.·Davis, C.·Meeker, A. K.·Heaphy, C. M.·Yegnasubramanian, S.·Dyer, M. A.·Zeineldin, M.
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Abstract

Acquiring a telomere maintenance mechanism is one of the hallmarks of high-risk neuroblastoma and commonly occurs by expressing telomerase (TERT). Telomerase-negative neuroblastoma has, characteristically, long telomeres and most utilize the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. Conversely, no discernable telomere maintenance mechanism is detected in a fraction of neuroblastoma with long telomeres, representing a phenomenon referred to as ever-shorter telomeres. Here, we show that, unlike most cancers, DNA of the TERT promoter is broadly hypomethylated in neuroblastoma. In telomerase-positive neuroblastoma cells, the hypomethylated DNA promoter is approximately 1.5-kb in length and is bound by hypermethylated TERT gene body and upstream intergenic sequences. The TERT locus shows active chromatin marks including H3K4me3, H3K27Ac, H3K14Ac, RNA PolII and BRD4 with low enrichment for the repressive mark, H3K27me3. Strikingly, in neuroblastoma with long telomeres, the hypomethylated region spans the entire TERT locus, including multiple nearby genes with enrichment for the repressive H3K27me3 chromatin mark. Furthermore, subtelomeric regions showed enrichment of repressive chromatin marks in neuroblastomas with long telomeres relative to those with short telomeres. These repressive marks were even more evident at the genic loci, suggesting a telomere position effect. Inhibiting H3K27 methylation by the EZH2 inhibitor, Tazemetostat, induced the expression of TERT, particularly in cell lines with long telomeres and H3K27me3 marks in the promoter region. Taken together, these data suggest that epigenetic regulation of TERT expression differs in neuroblastoma depending on the telomere maintenance status, and H3K27 methylation is important in repressing TERT expression in neuroblastoma with long telomeres.

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Graham, M. K., Xu, B., Davis, C., Meeker, A. K., Heaphy, C. M., Yegnasubramanian, S., Dyer, M. A., Zeineldin, M.. 2022-05-20. The TERT promoter is polycomb-repressed in neuroblastoma cells with long telomeres. https://doi.org/10.1101/2022.05.18.492493

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