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Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma

Modrek, A. S.; Chandradoss, K. R.; Do, C.; Ezhilarasan, R.; Sakellaropoulos, T.; Karp, J.; Ding, Y.; Zhang, Z.-Y.; Graciani, M.; Cova, G.; Phillips-Cremins, J. E.; Sulman, E. P.; Skok, J. A.

2025-06-24 genomics
10.1101/2025.06.18.660431 bioRxiv
Show abstract

DNA damage from routine cellular processes or exogenous insults can have a lasting impact on gene regulation beyond genetic mutations. The prevailing paradigm for the consequences of DNA damage repair revolves around restoration of the original genetic sequence, but long-term changes in chromatin configuration, gene expression and DNA modifications have not been analyzed. We introduced numerous, simultaneous Cas9-mediated DNA double strand breaks (DSBs) at defined locations in human glioblastoma cells and tracked both non-genetic and genetic alterations over time. Megabase-scale genomic alterations that endured two weeks after the initial damage were detected, involving a shift from transiently increased intra-TAD interactions to persistent long range cis and trans contacts, alterations in gene-expression and associated large structural variations. These findings reveal that widespread DNA damage, such as chemotherapy or radiotherapy, can trigger long-term genetic and non-genetic modifications which alter cellular function and may impact tumor outcome and the emergence of resistant cells.

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"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.