Epigenetic regulation during cancer transitions across 11 tumour types

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 . Although the genetic contributions to oncogenic transitions have been investigated, epigenetic dr...

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Published in:Nature (London) 2023-11, Vol.623 (7986), p.432-441
Main Authors: Terekhanova, Nadezhda V, Karpova, Alla, Liang, Wen-Wei, Strzalkowski, Alexander, Chen, Siqi, Li, Yize, Southard-Smith, Austin N, Iglesia, Michael D, Wendl, Michael C, Jayasinghe, Reyka G, Liu, Jingxian, Song, Yizhe, Cao, Song, Houston, Andrew, Liu, Xiuting, Wyczalkowski, Matthew A, Lu, Rita Jui-Hsien, Caravan, Wagma, Shinkle, Andrew, Naser Al Deen, Nataly, Herndon, John M, Mudd, Jacqueline, Ma, Cong, Sarkar, Hirak, Sato, Kazuhito, Ibrahim, Omar M, Mo, Chia-Kuei, Chasnoff, Sara E, Porta-Pardo, Eduard, Held, Jason M, Pachynski, Russell, Schwarz, Julie K, Gillanders, William E, Kim, Albert H, Vij, Ravi, DiPersio, John F, Puram, Sidharth V, Chheda, Milan G, Fuh, Katherine C, DeNardo, David G, Fields, Ryan C, Chen, Feng, Raphael, Benjamin J, Ding, Li
Format: Article
Language:English
Subjects:
Accessibility
Cancer
Cell Hypoxia
Cell Nucleus
Cells
Chromatin
Chromatin - genetics
Chromatin - metabolism
Cooperation
Enhancer Elements, Genetic - genetics
Epigenesis, Genetic - genetics
Epigenetics
Epithelial-Mesenchymal Transition
Estrogens
Estrogens - metabolism
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
GTPase-Activating Proteins - metabolism
Humans
Hypoxia
Keratin
Metastases
Metastasis
Mutation
Neoplasm Metastasis
Neoplasms - classification
Neoplasms - genetics
Neoplasms - pathology
Nuclei (cytology)
p53 Protein
Pancreatic cancer
Regulatory sequences
Regulatory Sequences, Nucleic Acid - genetics
Signal transduction
Single-Cell Analysis
Transcription Factors - metabolism
Transcriptomics
Tumors
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Summary: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 . 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-023-06682-5