Abstract
While radiation therapy offers strong anti-cancer benefits, it can also have serious side effects for children undergoing brain tumor treatment. These include disruptions in white matter development, delays in functional and cognitive growth, and an increased risk of secondary tumors within the area that was treated. Age-dependent susceptibility to these adverse effects is tightly linked to critical windows of neurodevelopment, particularly during the periods of active neural cell differentiation, maturation, and the rapid onset of myelination in infancy and early childhood. We previously demonstrated that oligodendrocyte precursor cells (OPCs) exhibit heightened sensitivity to IR-induced DNA damage compared to other neural stem/progenitor cells (NSPC) populations – a difference that is associated with their decreased ability to form RAD51 filaments (a critical step in RAD51-mediated homologous recombination repair of DNA double-strand breaks). Recently, we performed genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq) to map endogenous γH2AX binding sites—a sensitive marker of DNA damage response—in both S-phase OPCs and NSPCs. Our data identified 71,794 γH2AX-enriched regions in OPCs versus 29,154 in NSPCs, highlighting the elevated genotoxic stress burden in OPCs. Interestingly, we observed γH2AX binding is depleted at transcription start sites and transcription termination sites, however OPCs show more γH2AX peaks compare to NSPCs across all protein-coding genes. Furthermore, our data show cell type specific γH2AX binding sites. Together, these findings establish a comprehensive and unbiased genomic framework for elucidating the mechanisms underlying OPC vulnerability to DNA damage. Future studies will examine different DNA damage pattern in response to radiation.