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PreprintCC BY-NCbioRxiv

Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer

  • L. Nunes1
  • I. A. Eilertsen
  • R. Pinto
  • H. M. Vedeld
  • I. M. Bolstad
  • U. Saeed
  • O. H. Sjo
  • S. Yaqub
  • A. Nesbakken
  • K. Kryeziu
  • G. E. Lind
  • R. A. Lothe
1 more authors
  • A. Sveen
  1. 1Oslo University Hospital
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Abstract

Colorectal cancer (CRC) has high phenotypic plasticity, but regulatory mechanisms of aberrant cell states are not well described. We investigated DNA methylation-based regulation of cancer cell-intrinsic transcriptomic heterogeneity in 1,183 multiregional primary tumor samples, liver metastases and tumor organoids. Most genes with strong methylation-transcriptomic association reflected canonical promoter hypermethylation and expression repression related to the CpG island methylator phenotype (CIMP). However, promoter hypomethylation and overexpression of APOLD1 and ELF5 identified two largely non-overlapping subgroups of canonical CIMP-negative CRCs enriched with stem-like and transit-amplifying cell states. APOLD1 tumors were further highly proliferative while ELF5 tumors were slow-cycling and associated with good survival in early-stage disease. Target genes showed patient-specific expression changes in matched primary-metastasis samples, and ELF5 aberrant metastases showed ex vivo sensitivity to putative targeting of stem cells by PI3K/mTOR inhibition, fetal de-differentiation and transition into non-canonical intestinal states. This implicates focal promoter hypomethylation in phenotypic plasticity in CRC metastasis.

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Cite

BibTeXRIS
BibTeX
@misc{nunes2026epigenetic,
  title = {{Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer}},
  author = {L. Nunes and I. A. Eilertsen and R. Pinto and H. M. Vedeld and I. M. Bolstad and U. Saeed and O. H. Sjo and S. Yaqub and A. Nesbakken and K. Kryeziu and G. E. Lind and R. A. Lothe and A. Sveen},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.04.763625},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer
AU  - L. Nunes
AU  - I. A. Eilertsen
AU  - R. Pinto
AU  - H. M. Vedeld
AU  - I. M. Bolstad
AU  - U. Saeed
AU  - O. H. Sjo
AU  - S. Yaqub
AU  - A. Nesbakken
AU  - K. Kryeziu
AU  - G. E. Lind
AU  - R. A. Lothe
AU  - A. Sveen
PY  - 2026
DA  - 2026/11/04
PB  - bioRxiv
DO  - 10.64898/2026.11.04.763625
UR  - https://www.biorxiv.org/content/10.64898/2026.11.04.763625v1
AB  - Colorectal cancer (CRC) has high phenotypic plasticity, but regulatory mechanisms of aberrant cell states are not well described. We investigated DNA methylation-based regulation of cancer cell-intrinsic transcriptomic heterogeneity in 1,183 multiregional primary tumor samples, liver metastases and tumor organoids. Most genes with strong methylation-transcriptomic association reflected canonical promoter hypermethylation and expression repression related to the CpG island methylator phenotype (CIMP). However, promoter hypomethylation and overexpression of APOLD1 and ELF5 identified two largely non-overlapping subgroups of canonical CIMP-negative CRCs enriched with stem-like and transit-amplifying cell states. APOLD1 tumors were further highly proliferative while ELF5 tumors were slow-cycling and associated with good survival in early-stage disease. Target genes showed patient-specific expression changes in matched primary-metastasis samples, and ELF5 aberrant metastases showed ex vivo sensitivity to putative targeting of stem cells by PI3K/mTOR inhibition, fetal de-differentiation and transition into non-canonical intestinal states. This implicates focal promoter hypomethylation in phenotypic plasticity in CRC metastasis.
ER  -