TY - JOUR
T1 - Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
AU - Sheng, Taotao
AU - Ho, Shamaine Wei Ting
AU - Ooi, Wen Fong
AU - Xu, Chang
AU - Xing, Manjie
AU - Padmanabhan, Nisha
AU - Huang, Kie Kyon
AU - Ma, Lijia
AU - Ray, Mohana
AU - Guo, Yu Amanda
AU - Sim, Ngak Leng
AU - Anene-Nzelu, Chukwuemeka George
AU - Chang, Mei Mei
AU - Razavi-Mohseni, Milad
AU - Beer, Michael A.
AU - Foo, Roger Sik Yin
AU - Sundar, Raghav
AU - Chan, Yiong Huak
AU - Tan, Angie Lay Keng
AU - Ong, Xuewen
AU - Skanderup, Anders Jacobsen
AU - White, Kevin P.
AU - Jha, Sudhakar
AU - Tan, Patrick
N1 - Funding Information:
This work was supported by National Medical Research Council grants NMRC/STaR/0026/2015 and MOH-OFLCG18May-0003. Funding was also provided by the Cancer Science Institute of Singapore, NUS, under the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, and block funding was received from Duke-NUS Medical School and the Agency for Science, Technology, and Research (A*STAR).
Funding Information:
We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We also thank Liu Mo, Steve Rozen, Melissa Jane Fullwood and Heike Irmgard Grabsch for helpful discussions.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - CapSTARR-seq
KW - Enhancer heterogeneity
KW - Enhancer landscape
KW - Enhancer-promoter interactions
KW - Gastric cancer
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U2 - 10.1186/s13073-021-00970-3
DO - 10.1186/s13073-021-00970-3
M3 - Article
C2 - 34635154
AN - SCOPUS:85116765121
SN - 1756-994X
VL - 13
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 158
ER -