Abstract
Chromatin organization regulates transcription to influence cellular plasticity and cell fate. We explored whether chromatin nanoscale packing domains are involved in stemness and response to chemotherapy. Using an optical spectroscopic nanosensing technology we show that ovarian cancer-derived cancer stem cells (CSCs) display upregulation of nanoscale chromatin packing domains compared to non-CSCs. Cleavage under targets and tagmentation (CUT&Tag) sequencing with antibodies for repressive H3K27me3 and active H3K4me3 and H3K27ac marks mapped chromatin regions associated with differentially expressed genes. More poised genes marked by both H3K4me3 and H3K27me3 were identified in CSCs vs. non-CSCs, supporting increased transcriptional plasticity of CSCs. Pathways related to Wnt signaling and cytokine-cytokine receptor interaction were repressed in non-CSCs, while retinol metabolism and antioxidant response were activated in CSCs. Comparative transcriptomic analyses showed higher intercellular transcriptional heterogeneity at baseline in CSCs. In response to cisplatin, genes with low baseline expression levels underwent the highest upregulation in CSCs, demonstrating transcriptional plasticity under stress. Epigenome targeting drugs downregulated chromatin packing domains and promoted cellular differentiation. A disruptor of telomeric silencing 1-like (Dot1L) inhibitor blocked transcriptional plasticity, reversing stemness. These findings support that CSCs harbor upregulated chromatin packing domains, contributing to transcriptional and cell plasticity that epigenome modifiers can target.
| Original language | English (US) |
|---|---|
| Article number | 2407426 |
| Journal | Advanced Science |
| Volume | 12 |
| Issue number | 17 |
| DOIs | |
| State | Published - May 8 2025 |
Funding
This research was supported by funding from the National Institutes of Health/National Cancer Institute Grant Nos. U54CA268084-02 (to M.A., V.B., and D.M.), T32GM142604, and R01CA228272 (to V.B.), T32AI083216 (to L.M.A.), the National Science Foundation Grant No. EFMA-1830961 (to V.B.), the US Department of Veterans Affairs Grant No. BX000792-09A2 (to D.M.), the Ovarian Cancer Research Alliance postdoctoral fellowship to Y.W., the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center (to D.M.), and philanthropic support from Rob and Kristin Goldman, Susan Brice, the Christina Carinato Charitable Foundation, and David Sachs. Tumor specimens were procured through the Tissue Pathology Core and sequencing was performed in the NUSeq Core supported by Grant No. NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry analyses were performed in the Northwestern University \u2013 Flow Cytometry Core Facility supported by Cancer Center Support Grant No. NCI CA060553. This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at the Northwestern University which was jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. This material was based upon work performed by J.F. which was supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1842165. Any opinions, findings, conclusions, or recommendations expressed in this material were those of the authors and did not necessarily reflect the views of the National Science Foundation. The funders had no role in the study design, data collection, data analysis, the decision to publish, or the preparation of the paper. This research was supported by funding from the National Institutes of Health/National Cancer Institute Grant Nos. U54CA268084\u201002 (to M.A., V.B., and D.M.), T32GM142604, and R01CA228272 (to V.B.), T32AI083216 (to L.M.A.), the National Science Foundation Grant No. EFMA\u20101830961 (to V.B.), the US Department of Veterans Affairs Grant No. BX000792\u201009A2 (to D.M.), the Ovarian Cancer Research Alliance postdoctoral fellowship to Y.W., the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center (to D.M.), and philanthropic support from Rob and Kristin Goldman, Susan Brice, the Christina Carinato Charitable Foundation, and David Sachs. Tumor specimens were procured through the Tissue Pathology Core and sequencing was performed in the NUSeq Core supported by Grant No. NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry analyses were performed in the Northwestern University \u2013 Flow Cytometry Core Facility supported by Cancer Center Support Grant No. NCI CA060553. This research was supported in part through the computational resources and staff contributions provided for the Quest high\u2010performance computing facility at the Northwestern University which was jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. This material was based upon work performed by J.F. which was supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE\u20101842165. Any opinions, findings, conclusions, or recommendations expressed in this material were those of the authors and did not necessarily reflect the views of the National Science Foundation. The funders had no role in the study design, data collection, data analysis, the decision to publish, or the preparation of the paper.
Keywords
- cancer stem cells
- cell plasticity
- chromatin organization
- ovarian cancer
- transcriptional heterogeneity
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Chemical Engineering
- General Materials Science
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- General Engineering
- General Physics and Astronomy
