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Chemical-Induced Phase Transition and Global Conformational Reorganization of Chromatin [Hi-C]

ABSTRACT: Chemical-Induced Phase Transition and Global Conformational Reorganization of Chromatin [Hi-C]

PROVIDER: PRJNA922925 | ENA |

REPOSITORIES: ENA

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Chemical-Induced Phase Transition and Global Conformational Reorganization of Chromatin [Hi-C]

Project description:Chemicals or drugs were demonstrated to accumulate within biomolecule condensates formed through phase separation in cells. Here, we employed super-resolution imaging to search for chemicals that induce phase transition of chromatin at the microscale. We found that adriamycin (doxorubicin), a widely-used chemotherapeutic drug against malignancies, is able to induce local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments demonstrated that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically-associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces the phase transition of H1, forming fibrous aggregates in vitro. Our results reveal a new action mechanism of an anti-cancer drug discovered for decades, demonstrate the link between the physical properties of chromatin and gene expression, and suggest that interactions between drugs and biomolecules could exert profound effects on cells.

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Project description:Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been proposed. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. We studied the transcriptional and genome-wide chromatin organization changes in young, aged and mechanically rejuvenated fibroblasts using RNA-seq and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had reset their transcription to a younger cell state, showed a reorganization of the inter-chromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased contractility and reduced chromosome copy number variations, similar to younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Taken together, our results provide a multi-scale characterization of the chromatin reorganization that accompanies cellular aging and rejuvenation.

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