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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

View ORCID ProfileIrene Mota-Gómez, View ORCID ProfileJuan Antonio Rodríguez, Shannon Dupont, View ORCID ProfileOscar Lao, Johanna Jedamzick, Ralf Kuhn, View ORCID ProfileScott Lacadie, Sara Alexandra García-Moreno, View ORCID ProfileAlicia Hurtado, View ORCID ProfileRafael D. Acemel, View ORCID ProfileBlanche Capel, View ORCID ProfileMarc A. Marti-Renom, View ORCID ProfileDarío G. Lupiáñez
doi: https://doi.org/10.1101/2022.11.18.516861
Irene Mota-Gómez
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetics and Sex Development Group, Berlin, Germany
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Juan Antonio Rodríguez
2CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain
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Shannon Dupont
3Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
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Oscar Lao
4Institut de Biologia Evolutiva (UPF-CSIC), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain
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Johanna Jedamzick
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetics and Sex Development Group, Berlin, Germany
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Ralf Kuhn
5Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Scott Lacadie
6Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Computational Regulatory Genomics Group, Berlin, Germany
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Sara Alexandra García-Moreno
3Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
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Alicia Hurtado
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetics and Sex Development Group, Berlin, Germany
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Rafael D. Acemel
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetics and Sex Development Group, Berlin, Germany
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Blanche Capel
3Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
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Marc A. Marti-Renom
2CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain
7Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain
8Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain
9ICREA, 08010 Barcelona, Spain
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Darío G. Lupiáñez
1Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetics and Sex Development Group, Berlin, Germany
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  • For correspondence: dario.lupianez@mdc-berlin.de
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ABSTRACT

Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized. However, its epigenetic regulation is still largely unknown, thus limiting our understanding of a fundamental process for species propagation. Here we explore the 3D chromatin landscape of sex determination in vivo, by profiling FACS-sorted embryonic mouse gonadal populations, prior and after sex determination, in both sexes. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis that identifies 3D enhancer hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the enhancer hubs of hundreds of genes that display temporal- and sex-specific expression. Moreover, the identification of the 3D enhancer hubs allows the reconstruction of regulatory networks, revealing key transcription factors involved in sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, deletion of which results in male-to-female sex reversal with the upregulation of ovarian-specific markers and the initiation of meiosis. Thus, spatial auto-correlation analysis is an effective strategy to identify regulatory networks associated to biological processes and to further characterize the functional role of the 3D genome.

Competing Interest Statement

MAM-R receives consulting honoraria from Acuity Spatial Genomics, Inc.

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 November 18, 2022.
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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis
Irene Mota-Gómez, Juan Antonio Rodríguez, Shannon Dupont, Oscar Lao, Johanna Jedamzick, Ralf Kuhn, Scott Lacadie, Sara Alexandra García-Moreno, Alicia Hurtado, Rafael D. Acemel, Blanche Capel, Marc A. Marti-Renom, Darío G. Lupiáñez
bioRxiv 2022.11.18.516861; doi: https://doi.org/10.1101/2022.11.18.516861
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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis
Irene Mota-Gómez, Juan Antonio Rodríguez, Shannon Dupont, Oscar Lao, Johanna Jedamzick, Ralf Kuhn, Scott Lacadie, Sara Alexandra García-Moreno, Alicia Hurtado, Rafael D. Acemel, Blanche Capel, Marc A. Marti-Renom, Darío G. Lupiáñez
bioRxiv 2022.11.18.516861; doi: https://doi.org/10.1101/2022.11.18.516861

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