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Title: Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
Authors: Sheng, Taotao 
Ho, Shamaine Wei Ting 
Ooi, Wen Fong
Xu, Chang
Xing, Manjie
Padmanabhan, Nisha
Huang, Kie Kyon 
Ma, Lijia
Ray, Mohana
Guo, Yu Amanda
Sim, Ngak Leng
Anene-Nzelu, Chukwuemeka George
Chang, Mei Mei
Razavi-Mohseni, Milad
Beer, Michael A
Foo, Roger Sik Yin
Sundar, Raghav
Chan, Yiong Huak
Tan, Angie Lay Keng
Ong, Xuewen 
Skanderup, Anders Jacobsen
White, Kevin P
Jha, Sudhakar
Tan, Patrick 
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Enhancer landscape
Gastric cancer
Enhancer-promoter interactions
Enhancer heterogeneity
Issue Date: 11-Oct-2021
Publisher: BMC
Citation: Sheng, Taotao, Ho, Shamaine Wei Ting, Ooi, Wen Fong, Xu, Chang, Xing, Manjie, Padmanabhan, Nisha, Huang, Kie Kyon, Ma, Lijia, Ray, Mohana, Guo, Yu Amanda, Sim, Ngak Leng, Anene-Nzelu, Chukwuemeka George, Chang, Mei Mei, Razavi-Mohseni, Milad, Beer, Michael A, Foo, Roger Sik Yin, Sundar, Raghav, Chan, Yiong Huak, Tan, Angie Lay Keng, Ong, Xuewen, Skanderup, Anders Jacobsen, White, Kevin P, Jha, Sudhakar, Tan, Patrick (2021-10-11). Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer. GENOME MEDICINE 13 (1). ScholarBank@NUS Repository.
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.
ISSN: 1756994X
DOI: 10.1186/s13073-021-00970-3
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