Inverted logic of ecDNA localization converts nuclear periphery into oncogenic transcription hubs in cancer
- 1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA
Abstract
Extrachromosomal DNA (ecDNA) is a major driver of cancer pathogenesis, however, its spatial organization in the nucleus is not currently understood. Here we show that ecDNAs, in contrast to chromosomal DNA, preferentially localize to the nuclear periphery yet resist peripheral gene silencing. Single-molecule multi-omic sequencing and imaging-based CRISPR screening demonstrate enhanced ecDNA hub formation, H3K27ac and H3K9me3 bivalency, late DNA replication, long-range CpG hypomethylation, and increased transcriptional output when ecDNAs localize to the nuclear periphery. EcDNA anchors to the nuclear lamina through H3K9me3-dependent interactions with the Lamin B Receptor (LBR), which if interrupted, results in inward migration of ecDNA particles, reduced ecDNA congregation, and decreased transcription of ecDNA-encoded genes. These results reveal inherent advantages of the spatial organization of ecDNA that are not available to chromosomal DNA, enhancing ecDNA congregation and amplifying oncogenic transcriptional output, by localizing to the nuclear periphery of cancer cells.
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BibTeX
@misc{wang2026inverted,
title = {{Inverted logic of ecDNA localization converts nuclear periphery into oncogenic transcription hubs in cancer}},
author = {Y. Wang and X. Yan and N. E. Weiser and I. T.-L. Wong and S. Zhang and Y.-H. Huang and R. Li and K. Kraft and A. Gnanasekar and J. Tang and C. Chittenden and L. Bruckner and I. Noorani and C. Swanton and A. G. Henssen and A. B. Stergachis and N. Altemose and H. Y. Chang and P. S. Mischel},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.751063},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751063v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Inverted logic of ecDNA localization converts nuclear periphery into oncogenic transcription hubs in cancer
AU - Y. Wang
AU - X. Yan
AU - N. E. Weiser
AU - I. T.-L. Wong
AU - S. Zhang
AU - Y.-H. Huang
AU - R. Li
AU - K. Kraft
AU - A. Gnanasekar
AU - J. Tang
AU - C. Chittenden
AU - L. Bruckner
AU - I. Noorani
AU - C. Swanton
AU - A. G. Henssen
AU - A. B. Stergachis
AU - N. Altemose
AU - H. Y. Chang
AU - P. S. Mischel
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.751063
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.751063v1
AB - Extrachromosomal DNA (ecDNA) is a major driver of cancer pathogenesis, however, its spatial organization in the nucleus is not currently understood. Here we show that ecDNAs, in contrast to chromosomal DNA, preferentially localize to the nuclear periphery yet resist peripheral gene silencing. Single-molecule multi-omic sequencing and imaging-based CRISPR screening demonstrate enhanced ecDNA hub formation, H3K27ac and H3K9me3 bivalency, late DNA replication, long-range CpG hypomethylation, and increased transcriptional output when ecDNAs localize to the nuclear periphery. EcDNA anchors to the nuclear lamina through H3K9me3-dependent interactions with the Lamin B Receptor (LBR), which if interrupted, results in inward migration of ecDNA particles, reduced ecDNA congregation, and decreased transcription of ecDNA-encoded genes. These results reveal inherent advantages of the spatial organization of ecDNA that are not available to chromosomal DNA, enhancing ecDNA congregation and amplifying oncogenic transcriptional output, by localizing to the nuclear periphery of cancer cells.
ER -