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Epigenetic regulation during cancer transitions across 11 tumour types.

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.

SUBMITTER: Terekhanova NV

PROVIDER: S-EPMC10632147 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Epigenetic regulation during cancer transitions across 11 tumour types.

Terekhanova Nadezhda V NV Karpova Alla A Liang Wen-Wei WW Strzalkowski Alexander A Chen Siqi S Li Yize Y Southard-Smith Austin N AN Iglesia Michael D MD Wendl Michael C MC Jayasinghe Reyka G RG Liu Jingxian J Song Yizhe Y Cao Song S Houston Andrew A Liu Xiuting X Wyczalkowski Matthew A MA Lu Rita Jui-Hsien RJ Caravan Wagma W Shinkle Andrew A Naser Al Deen Nataly N Herndon John M JM Mudd Jacqueline J Ma Cong C Sarkar Hirak H Sato Kazuhito K Ibrahim Omar M OM Mo Chia-Kuei CK Chasnoff Sara E SE Porta-Pardo Eduard E Held Jason M JM Pachynski Russell R Schwarz Julie K JK Gillanders William E WE Kim Albert H AH Vij Ravi R DiPersio John F JF Puram Sidharth V SV Chheda Milan G MG Fuh Katherine C KC DeNardo David G DG Fields Ryan C RC Chen Feng F Raphael Benjamin J BJ Ding Li L

Nature 20231101 7986

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<sup>1-4</sup>. 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 transp ...[more]

PMID: 37914932

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Project description:BackgroundField cancerization is the process in which a population of normal or pre-malignant cells is affected by oncogenic alterations leading to progressive molecular changes that drive malignant transformation. Aberrant DNA methylation has been implicated in early cancer development in non-small cell lung cancer (NSCLC); however, studies on its role in field cancerization (FC) are limited. This study aims to identify FC-specific methylation patterns that could distinguish between pre-malignant lesions and tumor tissues in NSCLC.MethodsWe enrolled 52 patients with resectable NSCLC and collected resected tumor (TUM), tumor-adjacent (ADJ) and tumor-distant normal (DIS) tissue samples, among whom 36 qualified for subsequent analyses. Methylation levels were profiled by bisulfite sequencing using a custom lung-cancer methylation panel.ResultsADJ and DIS samples demonstrated similar methylation profiles, which were distinct from distinct from that of TUM. Comparison of TUM and DIS profiles led to identification of 1740 tumor-specific differential methylated regions (DMRs), including 1675 hypermethylated and 65 hypomethylated (adjusted P < 0.05). Six of the top 10 tumor-specific hypermethylated regions were associated with cancer development. We then compared the TUM, ADJ, and DIS to further identify the progressively aggravating aberrant methylations during cancer initiation and early development. A total of 332 DMRs were identified, including a predominant proportion of 312 regions showing stepwise increase in methylation levels as the sample drew nearer to the tumor (i.e. DIS < ADJ < TUM) and 20 regions showing a stepwise decrease pattern. Gene set enrichment analysis (GSEA) for KEGG and GO terms consistently suggested enrichment of DMRs located in transcription factor genes, suggesting a central role of epigenetic regulation of transcription factors in FC and tumorigenesis.ConclusionWe revealed distinct methylation patterns between pre-malignant lesions and malignant tumors, suggesting the essential role of DNA methylation as an early step in pre-malignant field defects. Moreover, our study also identified differentially methylated genes, especially transcription factors, that could potentially be used as markers for lung cancer screening and for mechanistic studies of FC and early cancer development.

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Epigenetic regulation during cancer transitions across 11 tumour types.

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Epigenetic regulation during cancer transitions across 11 tumour types.

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