TY  - JOUR
AU  - Stefanova, Maria E
AU  - Ing-Simmons, Elizabeth
AU  - Stefanov, Stefan
AU  - Flyamer, Ilya
AU  - Dorado Garcia, Heathcliff
AU  - Schöpflin, Robert
AU  - Henssen, Anton G
AU  - Vaquerizas, Juan M
AU  - Mundlos, Stefan
TI  - Doxorubicin Changes the Spatial Organization of the Genome around Active Promoters.
JO  - Cells
VL  - 12
IS  - 15
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DKFZ-2023-01631
SP  - 2001
PY  - 2023
AB  - In this study, we delve into the impact of genotoxic anticancer drug treatment on the chromatin structure of human cells, with a particular focus on the effects of doxorubicin. Using Hi-C, ChIP-seq, and RNA-seq, we explore the changes in chromatin architecture brought about by doxorubicin and ICRF193. Our results indicate that physiologically relevant doses of doxorubicin lead to a local reduction in Hi-C interactions in certain genomic regions that contain active promoters, with changes in chromatin architecture occurring independently of Top2 inhibition, cell cycle arrest, and differential gene expression. Inside the regions with decreased interactions, we detected redistribution of RAD21 around the peaks of H3K27 acetylation. Our study also revealed a common structural pattern in the regions with altered architecture, characterized by two large domains separated from each other. Additionally, doxorubicin was found to increase CTCF binding in H3K27 acetylated regions. Furthermore, we discovered that Top2-dependent chemotherapy causes changes in the distance decay of Hi-C contacts, which are driven by direct and indirect inhibitors. Our proposed model suggests that doxorubicin-induced DSBs cause cohesin redistribution, which leads to increased insulation on actively transcribed TAD boundaries. Our findings underscore the significant impact of genotoxic anticancer treatment on the chromatin structure of the human genome.
KW  - DSBs (Other)
KW  - Hi-C (Other)
KW  - Top2 (Other)
KW  - chemotherapy (Other)
KW  - doxorubicin (Other)
KW  - promoters (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37566080
C2  - pmc:PMC10417312
DO  - DOI:10.3390/cells12152001
UR  - https://inrepo02.dkfz.de/record/278397
ER  -