Epigenetic regulation during cancer transitions across 11 tumour types.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1005321 | ENA |
REPOSITORIES: ENA
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Project description:Chromatin accessibility plays an essential role in regulating gene expression and cellular identity, and its alterations have been implicated in driving oncogenic processes such as cancer initiation, progression, and metastasis1–4. While genetic aspects of cancer transitions have been explored, the role of epigenetic drivers remains less understood. To investigate the influence of chromatin architecture on cancer transitions, we generated an atlas of single-nucleus chromatin accessibility data (snATAC-seq) from 225 samples and matched single-cell/single-nucleus RNA expression (sc/snRNA-seq) from 206 samples across 11 cancer types. Analyzing over 1 million cells, we identified pan-cancer epigenetic drivers and transcriptional programs associated with transitions (regulatory regions of ABCC1, VEGFA, and GATA6, KLF6 and FOX-family TFs), as well as cancer type specific programs (regulatory regions of FGF19, ASAP2, EN1 and PBX3 TF). Differentially-accessible chromatin regions pinpointed genes and enriched pathways associated with major cancer transitions. For example, TP53, hypoxia, and TNFA signaling were linked to cancer initiation, while estrogen response, epithelial-mesenchymal transition (EMT), myogenesis, and apical junction were linked to metastatic transition. We also observed correlations between regulatory regions and genetic drivers across cancer types, suggesting their cooperation in cancer transition programs. This atlas furnishes a valuable resource for further investigation of the role of epigenetic programs in cancer initiation, progression, and metastasis.
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Project description: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.
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