PuSH - Publication Server of Helmholtz Zentrum München: X-linked deletion of <em>Crossfirre, Firre,</em> and <em>Dxz4</em> in vivo uncovers diverse phenotypes and combinatorial effects on autosomes.

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Hasenbein, T.P.* ; Hoelzl, S.* ; Smith, Z.D.* ; Gerhardinger, C.* ; Gonner, M.O.C.* ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Calzada-Wack, J. ; Dragano, N.R.V. ; da Silva Buttkus, P. ; Garrett, L. ; Hölter, S.M. ; Kraiger, M. ; Östereicher, M.A. ; Rathkolb, B. ; Sanz-Moreno, A. ; Spielmann, N. ; Wurst, W. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Meissner, A.* ; Engelhardt, S.* ; Rinn, J.L.* ; Andergassen, D.*

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

Nat. Commun. 15:10631 (2024)

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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.

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