X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes

Tim P. Hasenbein, Sarah Hoelzl, Zachary D. Smith, Chiara Gerhardinger, Marion O. C. Gonner, Antonio Aguilar-Pimentel, Oana V. Amarie, Lore Becker, Julia Calzada-Wack, Nathalia R. V. Dragano, Patricia da Silva-Buttkus, Lillian Garrett, Sabine M. Hölter, Markus Kraiger, Manuela A. Östereicher, Birgit Rathkolb, Adrián Sanz-Moreno, Nadine Spielmann, Wolfgang Wurst, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Alexander Meissner, Stefan Engelhardt, John L. Rinn () and Daniel Andergassen ()
Additional contact information
Tim P. Hasenbein: Technische Universität München
Sarah Hoelzl: Technische Universität München
Zachary D. Smith: Harvard University
Chiara Gerhardinger: Harvard University
Marion O. C. Gonner: Technische Universität München
Antonio Aguilar-Pimentel: Helmholtz Zentrum München
Oana V. Amarie: Helmholtz Zentrum München
Lore Becker: Helmholtz Zentrum München
Julia Calzada-Wack: Helmholtz Zentrum München
Nathalia R. V. Dragano: Helmholtz Zentrum München
Patricia da Silva-Buttkus: Helmholtz Zentrum München
Lillian Garrett: Helmholtz Zentrum München
Sabine M. Hölter: Helmholtz Zentrum München
Markus Kraiger: Helmholtz Zentrum München
Manuela A. Östereicher: Helmholtz Zentrum München
Birgit Rathkolb: Helmholtz Zentrum München
Adrián Sanz-Moreno: Helmholtz Zentrum München
Nadine Spielmann: Helmholtz Zentrum München
Wolfgang Wurst: Helmholtz Zentrum München
Valerie Gailus-Durner: Helmholtz Zentrum München
Helmut Fuchs: Helmholtz Zentrum München
Martin Hrabě de Angelis: Helmholtz Zentrum München
Alexander Meissner: Harvard University
Stefan Engelhardt: Technische Universität München
John L. Rinn: University of Colorado Boulder
Daniel Andergassen: Technische Universität München

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we perform one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination. Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we perform an extensive standardized phenotyping pipeline and uncover diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo.

Date: 2024
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DOI: 10.1038/s41467-024-54673-5

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