Enhancer activation from transposable elements in extrachromosomal DNA

Katerina Kraft; Sedona E Murphy; Matthew G Jones; Quanming Shi; Aarohi Bhargava-Shah; Christy Luong; King L Hung; Britney J He; Rui Li; Seung Kuk Park; Michael T Montgomery; Natasha E Weiser; Yanbo Wang; Jens Luebeck; Vineet Bafna; Jef D Boeke; Paul S Mischel; Alistair N Boettiger; Howard Y Chang

doi:10.1038/s41556-025-01788-6

Enhancer activation from transposable elements in extrachromosomal DNA

Nat Cell Biol. 2025 Nov;27(11):1914-1924. doi: 10.1038/s41556-025-01788-6. Epub 2025 Oct 21.

Authors

Katerina Kraft^#^{1

2}, Sedona E Murphy^#^{3

4

5

6}, Matthew G Jones^#^{1

7}, Quanming Shi^{1

2}, Aarohi Bhargava-Shah^{1

8}, Christy Luong^{1

9}, King L Hung^{1

10}, Britney J He¹, Rui Li¹, Seung Kuk Park¹¹, Michael T Montgomery^{3

12}, Natasha E Weiser⁸, Yanbo Wang⁸, Jens Luebeck¹³, Vineet Bafna¹³, Jef D Boeke¹⁴, Paul S Mischel⁸, Alistair N Boettiger⁴, Howard Y Chang^{15

16

17}

Affiliations

¹ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
² Amgen Research, South San Francisco, CA, USA.
³ Department of Genetics, Stanford University, Stanford, CA, USA.
⁴ Department of Developmental Biology, Stanford University, Stanford, CA, USA.
⁵ Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA.
⁶ Max Planck Institute For Molecular Genetics, Berlin, Germany.
⁷ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Sarafan ChEM-H Institute and Department of Pathology, Stanford University, Stanford, CA, USA.
⁹ Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
¹⁰ Department of Neuroscience, Scripps Research, La Jolla, CA, USA.
¹¹ Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
¹² Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
¹³ Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA.
¹⁴ Institute for Systems Genetics, NYU Langone Health, New York, NY, USA.
¹⁵ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
¹⁶ Department of Genetics, Stanford University, Stanford, CA, USA. howchang@stanford.edu.
¹⁷ Amgen Research, South San Francisco, CA, USA. howchang@stanford.edu.

^# Contributed equally.

Abstract

Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoural heterogeneity in aggressive cancers. While transposable element reactivation is common in cancer, its role on ecDNA remains unexplored. Here we map the 3D architecture of MYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements-genomic loci enriched for transposable elements that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified with MYC, which functions only in the ecDNA-amplified context. Using CRISPR-CATCH, CRISPR interference and reporter assays, we confirm its presence on ecDNA, enhancer activity and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumour evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy.

MeSH terms

Cell Line, Tumor
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
DNA Transposable Elements* / genetics
Enhancer Elements, Genetic*
Gene Amplification
Gene Expression Regulation, Neoplastic
Humans
Proto-Oncogene Proteins c-myc / genetics

Substances

DNA Transposable Elements
Proto-Oncogene Proteins c-myc
MYC protein, human

Abstract

MeSH terms

Substances

Grants and funding