Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer
Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer
Abstract BackgroundEnhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity – however, most predicted enhancer regions remain to be functionally tested. ResultsAnalyzing 128 epigenomic histone modification profiles of primary GC samples, normal gastric tissues, and GC cell lines, we report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are tumor-associated in vivo (>50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. Specifically, we identified cancer-relevant genes (e.g. ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4α as a master trans-acting factor associated with GC enhancer heterogeneity. ConclusionsOur study indicates that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, and provides insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.
Tan Patrick、Ong Xuewen、Jha Sudhakar、Ho Shamaine Wei Ting、Xu Chang、Xing Manjie、Huang Kie Kyon、Ma Lijia、Ray Mohana、Guo Yu Amanda、Razavi-Mohseni Milad、Leng Sim Ngak、Foo Roger Sik Yin、Sheng Taotao、Tan Angie Lay Keng、White Kevin P.、Beer Michael A.、Ooi Wen Fong、Skanderup Anders Jacobsen、Anene-Nzelu Chukwuemeka George、Padmanabhan Nisha、Chang Mei Mei
Cancer and Stem Cell Biology Program, Duke-NUS Medical School||Cancer Science Institute of Singapore, National University of Singapore||Epigenetic and Epitranscriptomic Regulation, Genome Institute of Singapore||SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore||Cellular and Molecular Research, National Cancer Centre||Singapore Gastric Cancer ConsortiumCancer and Stem Cell Biology Program, Duke-NUS Medical SchoolDepartment of Biochemistry, National University of Singapore||Cancer Science Institute of Singapore, National University of SingaporeCancer and Stem Cell Biology Program, Duke-NUS Medical School||Cancer Science Institute of Singapore, National University of SingaporeCancer and Stem Cell Biology Program, Duke-NUS Medical School||Cancer Science Institute of Singapore, National University of SingaporeCancer and Stem Cell Biology Program, Duke-NUS Medical School||Epigenetic and Epitranscriptomic Regulation, Genome Institute of SingaporeCancer and Stem Cell Biology Program, Duke-NUS Medical SchoolThe Institute for Genomics and Systems Biology, The University of ChicagoThe Institute for Genomics and Systems Biology, The University of ChicagoComputational and Systems Biology, Agency for Science Technology and Research, Genome Institute of SingaporeDepartment of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins UniversityComputational and Systems Biology, Agency for Science Technology and Research, Genome Institute of SingaporeCardiovascular Research Institute, National University Health System||Human Genetics, Genome Institute of SingaporeDepartment of Biochemistry, National University of Singapore||Cancer and Stem Cell Biology Program, Duke-NUS Medical SchoolCancer and Stem Cell Biology Program, Duke-NUS Medical SchoolThe Institute for Genomics and Systems Biology, The University of Chicago||Tempus LabsDepartment of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins UniversityEpigenetic and Epitranscriptomic Regulation, Genome Institute of SingaporeComputational and Systems Biology, Agency for Science Technology and Research, Genome Institute of SingaporeCardiovascular Research Institute, National University Health System||Human Genetics, Genome Institute of SingaporeCancer and Stem Cell Biology Program, Duke-NUS Medical SchoolComputational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore
肿瘤学基础医学生物科学研究方法、生物科学研究技术
Tan Patrick,Ong Xuewen,Jha Sudhakar,Ho Shamaine Wei Ting,Xu Chang,Xing Manjie,Huang Kie Kyon,Ma Lijia,Ray Mohana,Guo Yu Amanda,Razavi-Mohseni Milad,Leng Sim Ngak,Foo Roger Sik Yin,Sheng Taotao,Tan Angie Lay Keng,White Kevin P.,Beer Michael A.,Ooi Wen Fong,Skanderup Anders Jacobsen,Anene-Nzelu Chukwuemeka George,Padmanabhan Nisha,Chang Mei Mei.Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.06.09.447637.点此复制
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