EccDNA atlas in male mice reveals features protecting genes against transcription-induced eccDNA formation

Xue Liang; Gerard Arrey; Yating Qin; Lucía Álvarez-González; Judith Mary Hariprakash; Jie Ma; Sylvester Holt; Peng Han; Yonglun Luo; Hanbo Li; Aurora Ruiz-Herrera; Henriette Pilegaard; Birgitte Regenberg

doi:10.1038/s41467-025-57042-y

EccDNA atlas in male mice reveals features protecting genes against transcription-induced eccDNA formation

Xue Liang, Gerard Arrey, Yating Qin, Lucía Álvarez-González, Judith Mary Hariprakash, Jie Ma, Sylvester Holt, Peng Han, Yonglun Luo, Hanbo Li, Aurora Ruiz-Herrera, Henriette Pilegaard, Birgitte Regenberg^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

eccDNA is a driver of many cancers and a potential intermediate in other age-related disorders. However, little is known about the mechanisms underlying eccDNA formation in healthy tissue and how aging affects these processes. Here, we present an atlas of eccDNA across seven tissues of male mice spanning four ages. EccDNA correlates with open chromatin characterized by signatures of H3K27ac and H3K4me1. Additionally, the mutational load of eccDNA on genes correlates with tissue-specific transcription and increases logarithmically as a function of transcript level. Still, a population of intron-dense genes with many splice forms remains sheltered from eccDNA formation. We also find that the total number of eccDNA molecules does not increase as mice age, unlike other types of mutations. Our data reveal a link between eccDNA formation and transcript level that may drive gene architecture in mammals.

Originalsprog	Engelsk
Artikelnummer	1872
Tidsskrift	Nature Communications
Vol/bind	16
Udgave nummer	1
Antal sider	12
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-025-57042-y
Status	Udgivet - 2025

Bibliografisk note

Funding Information:
The authors thank the staff at BGI Qingdao sequencing facility for library preparation and sequencing, especially Wen Zhuang and Chunhua Li. We also thank Stine Ringholm for her help during dissection and the rest of the members of the Regenberg Laboratory for fruitful discussions of results and the manuscript. This work is supported by the Novo Nordisk Foundation (NNF18OC0053139 and NNF21OC0072023) to G.A., H.P., and B.R. GA also received funding from the European Union\u00B4s Horizon 2020 research and innovation program under the Marie Sk\u0142odowska-Curie grant agreement No 801199. X.L., Y.Q., and P.H. were funded by the Qingdao-Europe Advanced Institute for Life Sciences. AR-H. was funded by the Spanish Ministry of Science and Innovation (PID2020-112557GB-I00), the Ag\u00E8ncia de Gesti\u00F3 d\u2019Ajuts Universitaris i de Recerca (AGAUR, 2021SGR00122) and the Catalan Institution for Research and Advanced Studies (ICREA). LA-G. was supported by a FPI predoctoral fellowship from the Ministry of Economy and Competitiveness (PRE-2018-083257).

Funding Information:
B.R. is co-founder of CARE-DNA. X.L., Y.Q., P.H. are funded by Qingdao-Europe Advanced Institute for Life Sciences (QEI). J.M., Y.L., H.L. are or were employed by BGI. G.A., L.A.-G., J.M.H., S.H., A.R.-H., and H.P. declare that they have no known competing interests.

Publisher Copyright:
© The Author(s) 2025.

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10.1038/s41467-025-57042-yLicens: CC BY-NC-ND

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Citationsformater

Liang, X., Arrey, G., Qin, Y., Álvarez-González, L., Hariprakash, J. M., Ma, J., Holt, S., Han, P., Luo, Y., Li, H., Ruiz-Herrera, A., Pilegaard, H., & Regenberg, B. (2025). EccDNA atlas in male mice reveals features protecting genes against transcription-induced eccDNA formation. Nature Communications, 16(1), Artikel 1872. https://doi.org/10.1038/s41467-025-57042-y

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AU - Hariprakash, Judith Mary

AU - Ma, Jie

AU - Holt, Sylvester

AU - Han, Peng

AU - Luo, Yonglun

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AB - eccDNA is a driver of many cancers and a potential intermediate in other age-related disorders. However, little is known about the mechanisms underlying eccDNA formation in healthy tissue and how aging affects these processes. Here, we present an atlas of eccDNA across seven tissues of male mice spanning four ages. EccDNA correlates with open chromatin characterized by signatures of H3K27ac and H3K4me1. Additionally, the mutational load of eccDNA on genes correlates with tissue-specific transcription and increases logarithmically as a function of transcript level. Still, a population of intron-dense genes with many splice forms remains sheltered from eccDNA formation. We also find that the total number of eccDNA molecules does not increase as mice age, unlike other types of mutations. Our data reveal a link between eccDNA formation and transcript level that may drive gene architecture in mammals.

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