GSE106915
Epigenome editing of microsatellite repeat enhancers reveals specific regulatory functions and tumor dependencies [NRO-Seq]
Various types of repetitive sequences are dysregulated in cancer but their contributions to oncogenesis are yet to be determined. Here we combine nascent transcription profiling with epigenome editing to test the function of GGAA microsatellites in Ewing sarcoma, a pediatric bone cancer where the oncogenic fusion protein EWS-FLI1 induces chromatin features of active enhancers at this class of repeats. Silencing of chromatin through epigenome editing at specific GGAA repeats abolished local nascent transcription, decreased the expression of neighboring target genes and, in the case of a repeat associated with the SOX2 locus, reduced the growth of tumor xenografts. Our studies directly demonstrate that repeat elements can acquire enhancer functions in cancer and become critical components of oncogenic gene regulation programs. Overall design: Nascent transcription was measured using NRO-seq in Ewing sarcoma cells (A673 and SKNMC). EWS-FLI1 was knocked-down with lentiviral shRNA.