RRC ID 72501
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)