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  • Genetic elements promote retention of extrachromosomal DNA in cancer cells. Nature Sankar, V., Hung, K. L., Gnanasekar, A., Wong, I. T., Shi, Q., Kraft, K., Jones, M. G., He, B. J., Yan, X., Belk, J. A., Liu, K. J., Agarwal, S., Wang, S. K., Henssen, A. G., Mischel, P. S., Chang, H. Y. 2025

    Abstract

    Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division3-6 and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter-enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.

    View details for DOI 10.1038/s41586-025-09764-8

    View details for PubMedID 41261124

    View details for PubMedCentralID 9470669

  • Genetic elements promote retention of extrachromosomal DNA in cancer cells. bioRxiv : the preprint server for biology Sankar, V., Hung, K. L., Gnanasekar, A., Tsz-Lo Wong, I., Shi, Q., Kraft, K., Jones, M. G., He, B. J., Yan, X., Belk, J. A., Liu, K. J., Agarwal, S., Wang, S. K., Henssen, A. G., Mischel, P. S., Chang, H. Y. 2025

    Abstract

    Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer1,2. Circular megabase-sized ecDNAs lack centromeres and segregate stochastically during cell division3-6 yet persist over many generations. EcDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei over 40 years ago with unknown mechanism3,7. Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. We develop Retain-seq, a genome-scale assay that reveals thousands of human retention elements conferring generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromatin conformation capture show that retention elements physically interact with mitotic chromosomes at regions which are mitotically bookmarked by transcription factors and chromatin proteins, intermolecularly recapitulating promoter-enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated; targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, suggesting that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, revealing the principles of episome immortality intrinsic to the human genome.

    View details for DOI 10.1101/2025.10.10.681495

    View details for PubMedID 41278658

    View details for PubMedCentralID PMC12632332

  • Epigenomic State Transitions Characterize Tumor Progression in Mouse Lung Adenocarcinoma. Cancer cell LaFave, L. M., Kartha, V. K., Ma, S., Meli, K., Del Priore, I., Lareau, C., Naranjo, S., Westcott, P. M., Duarte, F. M., Sankar, V., Chiang, Z., Brack, A., Law, T., Hauck, H., Okimoto, A., Regev, A., Buenrostro, J. D., Jacks, T. 2020; 38 (2): 212

    Abstract

    Regulatory networks that maintain functional, differentiated cell states are often dysregulated in tumor development. Here, we use single-cell epigenomics to profile chromatin state transitions in a mouse model of lung adenocarcinoma (LUAD). We identify an epigenomic continuum representing loss of cellular identity and progression toward a metastatic state. We define co-accessible regulatory programs and infer key activating and repressive chromatin regulators of these cell states. Among these co-accessibility programs, we identify a pre-metastatic transition, characterized by activation of RUNX transcription factors, which mediates extracellular matrix remodeling to promote metastasis and is predictive of survival across human LUAD patients. Together, these results demonstrate the power of single-cell epigenomics to identify regulatory programs to uncover mechanisms and key biomarkers of tumor progression.

    View details for DOI 10.1016/j.ccell.2020.06.006

    View details for PubMedID 32707078

  • PAM50 Molecular Intrinsic Subtypes in the Nurses' Health Study Cohorts CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kensler, K. H., Sankar, V. N., Wang, J., Zhang, X., Rubadue, C. A., Baker, G. M., Parker, J. S., Hoadley, K. A., Stancu, A. L., Pyle, M. E., Collins, L. C., Hunter, D. J., Eliassen, A., Hankinson, S. E., Tamimi, R. M., Heng, Y. J. 2019; 28 (4): 798-806

    Abstract

    Modified median and subgroup-specific gene centering are two essential preprocessing methods to assign breast cancer molecular subtypes by PAM50. We evaluated the PAM50 subtypes derived from both methods in a subset of Nurses' Health Study (NHS) and NHSII participants; correlated tumor subtypes by PAM50 with IHC surrogates; and characterized the PAM50 subtype distribution, proliferation scores, and risk of relapse with proliferation and tumor size weighted (ROR-PT) scores in the NHS/NHSII.PAM50 subtypes, proliferation scores, and ROR-PT scores were calculated for 882 invasive breast tumors and 695 histologically normal tumor-adjacent tissues. Cox proportional hazards models evaluated the relationship between PAM50 subtypes or ROR-PT scores/groups with recurrence-free survival (RFS) or distant RFS.PAM50 subtypes were highly comparable between the two methods. The agreement between tumor subtypes by PAM50 and IHC surrogates improved to fair when Luminal subtypes were grouped together. Using the modified median method, our study consisted of 46% Luminal A, 18% Luminal B, 14% HER2-enriched, 15% Basal-like, and 8% Normal-like subtypes; 53% of tumor-adjacent tissues were Normal-like. Women with the Basal-like subtype had a higher rate of relapse within 5 years. HER2-enriched subtypes had poorer outcomes prior to 1999.Either preprocessing method may be utilized to derive PAM50 subtypes for future studies. The majority of NHS/NHSII tumor and tumor-adjacent tissues were classified as Luminal A and Normal-like, respectively.Preprocessing methods are important for the accurate assignment of PAM50 subtypes. These data provide evidence that either preprocessing method can be used in epidemiologic studies.

    View details for DOI 10.1158/1055-9965.EPI-18-0863

    View details for Web of Science ID 000481680500020

    View details for PubMedID 30591591

    View details for PubMedCentralID PMC6449178

  • Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons CELL REPORTS Wapinski, O. L., Lee, Q., Chen, A. C., Li, R., Corces, M., Ang, C., Treutlein, B., Xiang, C., Baubet, V., Suchy, F., Sankar, V., Sim, S., Quake, S. R., Dahmane, N., Wernig, M., Chang, H. Y. 2017; 20 (13): 3236–47

    Abstract

    How transcription factors (TFs) reprogram one cell lineage to another remains unclear. Here, we define chromatin accessibility changes induced by the proneural TF Ascl1 throughout conversion of fibroblasts into induced neuronal (iN) cells. Thousands of genomic loci are affected as early as 12 hr after Ascl1 induction. Surprisingly, over 80% of the accessibility changes occur between days 2 and 5 of the 3-week reprogramming process. This chromatin switch coincides with robust activation of endogenous neuronal TFs and nucleosome phasing of neuronal promoters and enhancers. Subsequent morphological and functional maturation of iN cells is accomplished with relatively little chromatin reconfiguration. By integrating chromatin accessibility and transcriptome changes, we built a network model of dynamic TF regulation during iN cell reprogramming and identified Zfp238, Sox8, and Dlx3 as key TFs downstream of Ascl1. These results reveal a singular, coordinated epigenomic switch during direct reprogramming, in contrast to stepwise cell fate transitions in development.

    View details for PubMedID 28954238