Abstract
Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR) EPN growth and diminishing H3K27ac states. These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG and an association with the ZRoncofusion in EPN. Mechanistic studies revealed extensive Sox9 and ZRpromoter co-occupancy, indicating functional synergy in promoting EPN tumorigenesis. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.
Overview
- The study investigates the role of Sox9 in regulating epigenomic states in high-grade glioma (HGG) and ependymoma (EPN) subtypes of brain tumors. The study uses autochthonous mouse models to compare the effects of Sox9 on HGG and EPN growth and epigenetic states. The study finds that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR) EPN growth and diminishing H3K27ac states. The study also identifies protein interactions between Sox9 and histone deacetylating complexes in HGG and an association between Sox9 and ZRoncofusion in EPN. The study aims to understand the molecular mechanisms responsible for the diverse epigenetic states in brain tumors and the role of Sox9 in regulating these states. The primary objective of the study is to identify the functional synergy between Sox9 and ZR in promoting EPN tumorigenesis.
Comparative Analysis & Findings
- The study compares the effects of Sox9 on HGG and EPN growth and epigenetic states. The study finds that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR) EPN growth and diminishing H3K27ac states. The study also identifies protein interactions between Sox9 and histone deacetylating complexes in HGG and an association between Sox9 and ZRoncofusion in EPN. The study finds that Sox9 plays divergent roles in HGG and EPN tumorigenesis, with Sox9 suppressing HGG growth and promoting ZR-mediated EPN growth. The study also identifies functional synergy between Sox9 and ZR in promoting EPN tumorigenesis.
Implications and Future Directions
- The study's findings have significant implications for understanding the molecular mechanisms responsible for the diverse epigenetic states in brain tumors and the role of Sox9 in regulating these states. The study identifies protein interactions between Sox9 and histone deacetylating complexes in HGG and an association between Sox9 and ZRoncofusion in EPN, providing insights into the molecular mechanisms underlying the divergent roles of Sox9 in HGG and EPN tumorigenesis. The study also identifies functional synergy between Sox9 and ZR in promoting EPN tumorigenesis, suggesting potential therapeutic targets for brain tumors. Future research directions could explore the role of Sox9 in other subtypes of brain tumors, investigate the therapeutic potential of targeting Sox9 and ZR in brain tumors, and explore the role of histone deacetylating complexes in brain tumorigenesis.