TY - JOUR T1 - Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer JF - Gut JO - Gut SP - 938 LP - 949 DO - 10.1136/gutjnl-2020-322835 VL - 71 IS - 5 AU - Elias Orouji AU - Ayush T Raman AU - Anand K Singh AU - Alexey Sorokin AU - Emre Arslan AU - Archit K Ghosh AU - Jonathan Schulz AU - Christopher Terranova AU - Shan Jiang AU - Ming Tang AU - Mayinuer Maitituoheti AU - Scot C Callahan AU - Praveen Barrodia AU - Katarzyna Tomczak AU - Yingda Jiang AU - Zhiqin Jiang AU - Jennifer S Davis AU - Sukhen Ghosh AU - Hey Min Lee AU - Laura Reyes-Uribe AU - Kyle Chang AU - Yusha Liu AU - Huiqin Chen AU - Ali Azhdarinia AU - Jeffrey Morris AU - Eduardo Vilar AU - Kendra S Carmon AU - Scott E Kopetz AU - Kunal Rai Y1 - 2022/05/01 UR - http://gut.bmj.com/content/71/5/938.abstract N2 - 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]. ER -