Dominant clones leverage developmental epigenomic states to drive ependymoma - PubMed
5 hours ago
- #epigenomics
- #oncology
- #ependymoma
- ZFTA-RELA (ZR) is the most recurrent genetic alteration in paediatric supratentorial ependymoma (EPN) and can initiate tumours in mice.
- Specific chromatin modules accessible during brain development make certain cell lineage programs susceptible to transformation by ZR.
- Combined single-nucleus assay for transposase-accessible chromatin and RNA sequencing (snMultiome) was performed on developing mouse forebrain and ZR-driven EPN.
- Transient progenitor cells regulated by PLAG/L family transcription factors are at risk of neoplastic transformation.
- ZR or other PLAG/L family motifs targeting fusion oncoproteins lead to persistent chromatin accessibility and oncogene expression.
- Mouse and human ZR EPN show significant cell type heterogeneity with incomplete neurogenic and gliogenic differentiation.
- A small percentage of cycling progenitor-like or radial glial-like cells establish a putative tumour cell hierarchy.
- In vivo lineage tracing identified dominant neoplastic clones that drive tumour growth and establish the EPN cellular hierarchy.
- The study identifies critical developmental epigenomic states for fusion-oncoprotein-driven transformation and their role in tumour progression.