RT Journal Article SR Electronic T1 Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 938 OP 949 DO 10.1136/gutjnl-2020-322835 VO 71 IS 5 A1 Elias Orouji A1 Ayush T Raman A1 Anand K Singh A1 Alexey Sorokin A1 Emre Arslan A1 Archit K Ghosh A1 Jonathan Schulz A1 Christopher Terranova A1 Shan Jiang A1 Ming Tang A1 Mayinuer Maitituoheti A1 Scot C Callahan A1 Praveen Barrodia A1 Katarzyna Tomczak A1 Yingda Jiang A1 Zhiqin Jiang A1 Jennifer S Davis A1 Sukhen Ghosh A1 Hey Min Lee A1 Laura Reyes-Uribe A1 Kyle Chang A1 Yusha Liu A1 Huiqin Chen A1 Ali Azhdarinia A1 Jeffrey Morris A1 Eduardo Vilar A1 Kendra S Carmon A1 Scott E Kopetz A1 Kunal Rai YR 2022 UL http://gut.bmj.com/content/71/5/938.abstract AB Objective Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.Design We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.Results We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.Conclusion Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.Data are available in a public, open access repository. ChIP-seq, RNA-seq and Hi-ChIP datasets that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) database with the accession codes as follows: GSE136889 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136889], GSE88945 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE88945], GSE106500 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE106500] and GSE136044 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136044].