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 DeenJohn 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, Li Ding

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 metastasis 1–4. 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.

Original languageEnglish
Pages (from-to)432-441
Number of pages10
JournalNature
Volume623
Issue number7986
DOIs
StatePublished - Nov 9 2023

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