論文 - 詳細
RRC ID | 72501 |
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著者 | Sheng T, Ho SWT, Ooi WF, Xu C, Xing M, Padmanabhan N, Huang KK, Ma L, Ray M, Guo YA, Sim NL, Anene-Nzelu CG, Chang MM, Razavi-Mohseni M, Beer MA, Foo RSY, Sundar R, Chan YH, Tan ALK, Ong X, Skanderup AJ, White KP, Jha S, Tan P. |
タイトル | Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer. |
ジャーナル | Genome Med |
Abstract |
BACKGROUND:Enhancers 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. METHODS:We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions. RESULTS:We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated in vivo (> 50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying 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. We identified cancer-relevant genes (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. CONCLUSIONS:Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity. |
巻・号 | 13(1) |
ページ | 158 |
公開日 | 2021-10-11 |
DOI | 10.1186/s13073-021-00970-3 |
PII | 10.1186/s13073-021-00970-3 |
PMID | 34635154 |
PMC | PMC8504099 |
MeSH | ADP-Ribosylation Factors / genetics ADP-Ribosylation Factors / metabolism Acetylation Cell Line, Tumor Cell Proliferation Chromatin Enhancer Elements, Genetic* Epigenomics* Gene Expression Regulation, Neoplastic Genomics Histones / metabolism Humans Inhibitor of Growth Protein 1 / genetics Inhibitor of Growth Protein 1 / metabolism Oncogenes Promoter Regions, Genetic RNA-Seq Stomach Neoplasms / genetics* Transcriptome Whole Genome Sequencing |
IF | 10.886 |
リソース情報 | |
ヒト・動物細胞 | LMSU(RCB1062) |