Chromatin Organization Governs Transcriptional Response and Plasticity of Cancer Stem Cells

作者：Yinu Wang, Jane Frederick, Karla Medina, Elizabeth T. Bartom, Luay M. Almassalha, Yaqi Zhang, Greta Wodarcyk, Hao Huang, I Chae Ye, Ruyi Gong, Cody L. Dunton, Alex Duval, Paola Carrillo Gonzalez, Joshua K. Pritchard, John Carinato, Iuliia Topchu, Junzui Li, Zhe Ji, Mazhar Adli, Vadim Backman, Daniela Matei · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202407426 · 被引用次数：12 · 研究领域：Cancer Cells and Metastasis、Genomics and Chromatin Dynamics、RNA Interference and Gene Delivery

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 chr...