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.
Show abstract
MYCN-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.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor 98%
- Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops 96%
- Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer 95%
Similar papers in this journal
- EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition 96%
- High throughput screening identifies SOX2 as a Super Pioneer Factor that inhibits DNA methylation maintenance at its binding sites 95%
- The RING Finger E3 Ligase RNF25 Protects DNA Replication Forks Independently of its Canonical Roles in Ubiquitin Signaling 95%
Similar papers in this journal
- Sequential deregulation of histone marks, chromatin accessibility and gene expression in response to PROTAC-induced degradation of ASH2L 96%
- PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma 94%
- A Vector System Encoding Histone H3 Mutants Facilitates Manipulations of the Neuronal Epigenome 94%
Similar papers in this journal
- H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells 96%
- Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase 96%
- YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1 mediated reprogramming of bone mesenchymal stem cells 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.