8-oxodG accumulation within super-enhancers marks fragile CTCF-mediated chromatin loops

• Main Authors: Ambrosio, S. (Author), Amente, S. (Author), Chiariello, A.M (Author), Gorini, F. (Author), Lania, L. (Author), Majello, B. (Author), Nicodemi, M. (Author), Scala, G. (Author)
• Format: Article
• Language: English
• Published: Oxford University Press 2022
• Online Access: View Fulltext in Publisher

 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a major product of the DNA oxidization process, has been proposed to have an epigenetic function in gene regulation and has been associated with genome instability. NGS-based methodologies are contributing to the characterization of the 8-oxodG function in the genome. However, the 8-oxodG epigenetic role at a genomic level and the mechanisms controlling the genomic 8-oxodG accumulation/maintenance have not yet been fully characterized. In this study, we report the identification and characterization of a set of enhancer regions accumulating 8-oxodG in human epithelial cells. We found that these oxidized enhancers are mainly super-enhancers and are associated with bidirectional-transcribed enhancer RNAs and DNA Damage Response activation. Moreover, using ChIA-PET and HiC data, we identified specific CTCF-mediated chromatin loops in which the oxidized enhancer and promoter regions physically associate. Oxidized enhancers and their associated chromatin loops accumulate endogenous double-strand breaks which are in turn repaired by NHEJ pathway through a transcription-dependent mechanism. Our work suggests that 8-oxodG accumulation in enhancers-promoters pairs occurs in a transcription-dependent manner and provides novel mechanistic insights on the intrinsic fragility of chromatin loops containing oxidized enhancers-promoters interactions. © 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.