Epigenetic regulation during cancer transitions across 11 tumour types

Nadezhda V. Terekhanova, Alla Karpova, Wen-Wei Liang, Alexander Strzalkowski, Siqi Chen, Yize Li, Austin N. Southard-Smith, Michael D. Iglesia, Michael C. Wendl, Reyka G. Jayasinghe, Jingxian Liu, Yizhe Song, Song Cao, Andrew Houston, Xiuting Liu, Matthew A. Wyczalkowski, Rita Jui-Hsien Lu, Wagma Caravan, Andrew Shinkle, Nataly Naser Al Deen, John M. Herndon, Jacqueline Mudd, Cong Ma, Hirak Sarkar, Kazuhito Sato, Omar M. Ibrahim, Chia-Kuei Mo, Sara E. Chasnoff, Eduard Porta-Pardo, Jason M. Held, Russell Pachynski, Julie K. Schwarz, William E. Gillanders, Albert H. Kim, Ravi Vij, John F. DiPersio, Sidharth V. Puram, Milan G. Chheda, Katherine C. Fuh, David G. DeNardo, Ryan C. Fields (), Feng Chen (), Benjamin J. Raphael () and Li Ding ()
Additional contact information
Nadezhda V. Terekhanova: Washington University in St Louis
Alla Karpova: Washington University in St Louis
Wen-Wei Liang: Washington University in St Louis
Alexander Strzalkowski: Princeton University
Siqi Chen: Washington University in St Louis
Yize Li: Washington University in St Louis
Austin N. Southard-Smith: Washington University in St Louis
Michael D. Iglesia: Washington University in St Louis
Michael C. Wendl: Washington University in St Louis
Reyka G. Jayasinghe: Washington University in St Louis
Jingxian Liu: Washington University in St Louis
Yizhe Song: Washington University in St Louis
Song Cao: Washington University in St Louis
Andrew Houston: Washington University in St Louis
Xiuting Liu: Washington University in St Louis
Matthew A. Wyczalkowski: Washington University in St Louis
Rita Jui-Hsien Lu: Washington University in St Louis
Wagma Caravan: Washington University in St Louis
Andrew Shinkle: Washington University in St Louis
Nataly Naser Al Deen: Washington University in St Louis
John M. Herndon: Washington University in St Louis
Jacqueline Mudd: Washington University in St Louis
Cong Ma: Princeton University
Hirak Sarkar: Princeton University
Kazuhito Sato: Washington University in St Louis
Omar M. Ibrahim: Washington University in St Louis
Chia-Kuei Mo: Washington University in St Louis
Sara E. Chasnoff: Washington University in St Louis
Eduard Porta-Pardo: Josep Carreras Leukaemia Research Institute
Jason M. Held: Washington University in St Louis
Russell Pachynski: Washington University in St Louis
Julie K. Schwarz: Washington University in St Louis
William E. Gillanders: Washington University in St Louis
Albert H. Kim: Washington University in St Louis
Ravi Vij: Washington University in St Louis
John F. DiPersio: Washington University in St Louis
Sidharth V. Puram: Washington University in St Louis
Milan G. Chheda: Washington University in St Louis
Katherine C. Fuh: University of California, San Francisco
David G. DeNardo: Washington University in St Louis
Ryan C. Fields: Washington University in St Louis
Feng Chen: Washington University in St Louis
Benjamin J. Raphael: Princeton University
Li Ding: Washington University in St Louis

Nature, 2023, vol. 623, issue 7986, 432-441

Abstract: Abstract Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1–4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial–mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Date: 2023
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DOI: 10.1038/s41586-023-06682-5

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