5-hydroxymethylcytosine deposition mediates Polycomb Repressive Complex 2 function in MYCN-amplified neuroblastoma
5-hydroxymethylcytosine deposition mediates Polycomb Repressive Complex 2 function in MYCN-amplified neuroblastoma
Chennakesavalu, M.; Lopez, G. L.; Gupta, V.; Moore, K.; Xue, Y.; Majowka, J.; Veeravalli, S.; Borchert, R.; Pomaville, M.; Chlenski, A.; He, C.; Piunti, A.; Applebaum, M.
AbstractMYCN-amplification is a strong predictor of poor prognosis in neuroblastoma, an embryonal malignancy that accounts for 15% of pediatric cancer deaths. Here, we found that MYCN-amplified neuroblastoma tumors had increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb Repressive Complex 2 (PRC2) target genes. 5-hmC and H3K27me3, a catalytic product of PRC2, directly co-localized at the nucleosomal level in MYCN-amplified neuroblastoma. Genes with co-localization of 5-hmC/H3K27me3 were involved in development related pathways and were transcriptionally repressed in MYCN-amplified neuroblastoma. Inhibition of 5-hmC deposition resulted in a loss of H3K27me3 on protein-coding genes and sensitized neuroblastoma to DNA demethylating agents. 5-hmC deposition predisposed H3K27me3 marked genes to transcriptional activation upon PRC2 inhibition with tazemetostat. Low expression of genes marked by 5-hmC/H3K27me3 was associated with poor clinical outcome. Our results suggest that 5-hmC/H3K27me3 co-operate to repress mediators of development highlighting a novel link between DNA and chromatin modifications with potential therapeutic implications in MYCN-amplified neuroblastoma.