Deciphering functional differences in the mechanisms driving focal oncogene amplification
New tool published by team eDyNAmiC.
Rewiring oncogene enhancers and 3D genome organisation in primary cancers
New findings from team eDyNAmiC
Team eDyNAmiC are taking on the extrachromosomal DNA challenge. Here, future leaders and first authors Katie Yost and Yanding Zhao take us through the findings of the team’s latest paper published in Nature Genetics, which uses HiChIP to investigate 3D genome rearrangement in primary cancers. By mapping enhancer connectomes, the work demonstrates that ecDNA is associated with more extensive enhancer rewiring than other types of rearrangements.
The problem
Structural variations (SVs) are widespread in cancer genomes and drive tumour progression via oncogene amplification, notably through the formation of extrachromosomal DNA (ecDNA). In addition to increased gene copy number, SVs can dramatically alter the connectivity between genes and distal enhancers. However, assessing how genomic rearrangements affect gene regulation in cancer remains difficult due to ambiguity in mapping enhancers to their target genes and the diversity of patient-specific genetic alterations.
Integrating technologies to model oncogene expression
In this paper, we investigated the three-dimensional (3D) genome organisation of primary cancers using HiChIP, a chromatin conformation technique targeting histone H3 lysine 27 acetylation (H3K27ac) to simultaneously capture enhancer activity and interactions with target genes. By integrating these data with whole-genome sequencing, single-cell chromatin accessibility, and transcriptomic profiling from The Cancer Genome Atlas (TCGA), we aimed to understand how genome topology contributes to gene expression alterations in cancer.
We found that enhancer-promoter loops exhibited substantial variability between cancer types, highlighting their dynamic regulatory function and reflecting tissue-specific patterns of gene regulation. By integrating DNA copy number, enhancer activity, and RNA expression, we found that while gene amplification can promote overexpression for a subset of oncogenes, such as KRAS, enhancer activation and rewiring more frequently account for aberrant oncogene expression across cancers. We also identified noncoding somatic mutations capable of generating novel transcription factor binding sites, resulting in increased enhancer activity in an allele-specific manner to promote oncogene overexpression.
Extensive enhancer rewiring driven by structural rearrangements
We further examined the impact of SVs on enhancer connectivity, with a particular focus on extrachromosomal DNA (ecDNA). Unlike chromosomal SVs that are limited by topologically associating domain (TAD) boundaries, ecDNAs engage in intermolecular transcriptional regulation and are characterised by increased chromatin accessibility, enabling high levels of oncogene expression. While both chromosomal SVs and ecDNA formation can result in novel enhancer-promoter contacts, ecDNA is associated with more extensive enhancer rewiring than other types of rearrangements, suggesting that ecDNA formation underlies more dramatic regulatory alterations that other types of genomic rearrangements.
Through this work, we expand the current understanding of 3D genome organisation in cancer and demonstrate how genome architecture, regulatory element dynamics, and structural genome alterations converge to shape oncogenic transcriptional programs. Our mapping of enhancer connectomes in primary tumours offers a valuable framework for dissecting gene regulation and may inform future therapeutic strategies that incorporate 3D genome architecture into precision medicine.
About Katie Yost
I am a cancer biologist interested in understanding gene regulation and cellular dynamics in cancer. I completed my PhD in Cancer Biology at Stanford University advised by Howard Chang and am currently a postdoctoral fellow at the Whitehead Institute in Jonathan Weissman’s lab.
My research uses genomic technologies and computational analyses to decode regulatory dynamics as well as immune responses in cancer to gain novel insights into the biological processes that underlie cancer progression and therapeutic response. As part of Cancer Grand Challenges team eDyNAmiC, I have investigated how ecDNA uniquely impacts oncogene regulation.
About Yanding Zhao
I earned my PhD in Genetics from Dartmouth College and am currently a postdoctoral researcher at Stanford University in the lab of Howard Chang. My research is driven by a deep interest in how cancer evolves, with a particular focus on the roles of genomics and 3D chromatin architecture.
Throughout my career, I’ve developed computational tools to explore how genetic mutations — especially in non-coding regions — disrupt gene regulation in cancer. More recently, my work has centered on ecDNA, a potent driver of oncogene amplification and tumour progression. By integrating computational biology with experimental methods, my goal is to unravel how genome structure shapes cancer evolution and to help lay the groundwork for more effective, targeted cancer therapies.
Featured Publication
Three-dimensional genome landscape of primary human cancers, Nature Genetics
Through Cancer Grand Challenges eDyNAmiC is funded by Cancer Research UK, the National Cancer Institute and Emerson Collective.
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