Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing
Summary
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.
Overall design
Data includes snATAC-seq and snRNA-seq for 24 clear cell renal carcinoma samples, 4 normal kidney samples, 18 glioblastoma samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC)
***Will submit raw data files to either GDC or CDS***
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