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The regulatory landscapes of human ovarian ageing

Chen Jin, Xizhe Wang, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Seungsoo Kim, Daniela Contreras, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, View ORCID ProfileMichael G. Rosenfeld, Yousin Suh
doi: https://doi.org/10.1101/2022.05.18.492547
Chen Jin
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Xizhe Wang
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Adam D. Hudgins
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Amir Gamliel
2Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA, USA
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Mingzhuo Pei
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Seungsoo Kim
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Daniela Contreras
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Jan Hoeijmakers
3Department Molecular Genetics, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
4Princess Máxima Center for Pediatric Oncology, Oncode Institute, Utrecht, The Netherlands
5Institute for Genome Stability in Ageing and Disease, Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University Hospital of Cologne, Cologne, Germany
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Judith Campisi
6Buck Institute for Research on Aging, Novato, CA, USA
7Lawrence Berkeley National Laboratory, Berkeley, CA, USA
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Rogerio Lobo
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Zev Williams
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
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Michael G. Rosenfeld
2Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA, USA
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  • ORCID record for Michael G. Rosenfeld
Yousin Suh
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY
8Department of Genetics and Development, Columbia University Medical Center, New York, NY
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  • For correspondence: ys3214@cumc.columbia.edu
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Summary paragraph

The ovary is the first organ to age in the human body, affecting both fertility and overall health in women1-8. However, the biological mechanisms underlying human ovarian ageing remain poorly understood. Here we performed single-nuclei multi-omics analysis of young and reproductively aged human ovaries to understand the molecular and cellular basis of ovarian ageing in humans. Our analysis reveals coordinated changes in transcriptomic output and chromatin accessibility across cell types during ageing, including elevated mTOR and MAPK signaling, decreased activity of the oxidative phosphorylation and DNA damage repair pathways, and an increased signature of cellular senescence. By constructing cell type-specific regulatory networks, we uncover enhanced activity of the transcription factor CEBPD across cell types in the aged ovary, with a corresponding significant loss of activity of most cell identity-associated transcription factors. Moreover, by performing integrative analyses of our single-nuclei multi-omics data with common genetic variants associated with age at natural menopause (ANM) from genome-wide association studies, we demonstrate a global impact of functional variants on changes in gene regulatory networks across ovarian cell types. Finally, we nominate about a dozen of functional non-coding variants, their target genes and cell types and regulatory mechanisms that underlie genetic association with ANM. This work provides a comprehensive multimodal landscape of human ovarian ageing and mechanistic insights into inherited variation of ANM.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 19, 2022.
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The regulatory landscapes of human ovarian ageing
Chen Jin, Xizhe Wang, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Seungsoo Kim, Daniela Contreras, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G. Rosenfeld, Yousin Suh
bioRxiv 2022.05.18.492547; doi: https://doi.org/10.1101/2022.05.18.492547
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The regulatory landscapes of human ovarian ageing
Chen Jin, Xizhe Wang, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Seungsoo Kim, Daniela Contreras, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G. Rosenfeld, Yousin Suh
bioRxiv 2022.05.18.492547; doi: https://doi.org/10.1101/2022.05.18.492547

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