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Original research
Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer
  1. Elias Orouji1,
  2. Ayush T Raman1,2,3,
  3. Anand K Singh1,
  4. Alexey Sorokin4,
  5. Emre Arslan1,
  6. Archit K Ghosh1,5,
  7. Jonathan Schulz1,5,
  8. Christopher Terranova1,
  9. Shan Jiang1,
  10. Ming Tang1,
  11. Mayinuer Maitituoheti1,
  12. Scot C Callahan1,
  13. Praveen Barrodia1,
  14. Katarzyna Tomczak1,
  15. Yingda Jiang1,5,
  16. Zhiqin Jiang4,
  17. Jennifer S Davis4,
  18. Sukhen Ghosh6,
  19. Hey Min Lee4,5,
  20. Laura Reyes-Uribe7,
  21. Kyle Chang7,
  22. Yusha Liu8,
  23. Huiqin Chen4,
  24. Ali Azhdarinia6,
  25. Jeffrey Morris9,
  26. Eduardo Vilar5,7,
  27. Kendra S Carmon5,6,
  28. Scott E Kopetz4,5,
  29. Kunal Rai1,3,5
  1. 1 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2 Broad Institute of MIT and Harvard, Cambridge, Massachussetts, USA
  3. 3 Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, Texas, USA
  4. 4 Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5 MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6 Center for Translational Cancer Research, University of Texas Health Science Center at Houston, Houston, Texas, USA
  7. 7 Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  8. 8 University of Chicago Medical Center, Chicago, Illinois, USA
  9. 9 University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Kunal Rai, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; krai{at}mdanderson.org

Abstract

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.

  • colorectal cancer
  • cancer genetics
  • colon carcinogenesis
  • adenocarcinoma

Data availability statement

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].

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Data availability statement

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].

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Footnotes

  • Twitter @aayushraman, @ArchitGhosh1, @mahinur mattohti

  • EO, ATR and AKS contributed equally.

  • Contributors EO conceived, conceptualised and designed the study, planned and carried out experiments, analysed data, prepared figures and wrote the manuscript. ATR conceptualised and designed the study, performed computational analysis, prepared figures and wrote the manuscript. AKS contributed to study design, carried out experiments, performed computational analysis, prepared figures and wrote the manuscript. AS performed PDX experiments. EA performed computational analysis for CMS2 classification. AKG performed the 3C experiments and edited the manuscript. JS performed peak length analysis. MT helped with informatics analysis. CT, SCC, MM, KT, ZJ, JSD, SG, HML, LR-U, KC, YL, HC, AA, EA, YJ, SJ provided technical help. JM, EV, KSC and SK contributed to study design and provided reagents. KR conceived, conceptualised and designed the study, performed experiments, evaluated data, made figures and wrote the manuscript. All the authors edited the manuscript.

  • Funding This work was supported by ACS research scholar award, CPRIT IIRA award (RP200390), a Career Development Award from MDACC GI SPORE to KR. We thank Integromics group, the Advanced Technology Genomics Core Facility (NCI Grant CA016672(ATGC), the Research Animal Support Facility, the Advanced Microscopy Core Facility (funded by NIH S10 RR029552), Functional Genomics Core (NCI Cancer Centre Support Grant (P30 CA016672) and MD Anderson Cancer Centre Clinical Core.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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