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Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription

Yanfen Zhu1, Amit D Gujar1, Chee-Hong Wong1

  • 1The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.

Cancer Cell
|April 9, 2021
PubMed

Insights

Extrachromosomal DNA (ecDNA) acts as mobile enhancers in cancer, driving gene expression and tumor progression. These circular DNA elements form extensive interactions, influencing chromosomal genes and oncogenes.

Area of Science:

  • Cancer Genomics
  • Epigenetics
  • Molecular Biology

Background:

  • Extrachromosomal DNA (ecDNA) is a significant but understudied driver of cancer.
  • Understanding ecDNA's role in gene regulation is crucial for cancer therapy.

Purpose of the Study:

  • To characterize genome-wide chromatin interactions mediated by ecDNA.
  • To investigate how ecDNA impacts transcriptional programs in cancer.

Main Methods:

  • Utilized ChIA-PET and ChIA-Drop assays to map ecDNA-mediated chromatin contacts.
  • Analyzed ecDNA interactions in glioblastoma and prostate cancer models.
  • Employed single-molecule resolution to identify chromosomal targets of ecDNA.

Main Results:

  • Identified widespread intra-ecDNA and genome-wide chromosomal interactions in cancer cells.
  • Observed high H3K27ac signals at ecDNA-chromatin contact sites, correlating with increased gene expression.
  • Demonstrated that synthetic ecDNA enhancers activate chromosomal gene transcription genome-wide.
  • Found ecDNA interactions associate with actively expressed oncogenes.

Conclusions:

  • ecDNA functions as mobile transcriptional enhancers, promoting tumor progression.
  • ecDNA may represent a novel mechanism of synthetic aneuploidy in cancer transcription control.
Keywords:
ChIA-DropChIA-PETchromatin interactionsecDNAmobile enhancers

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