Journal Article

DZNE-2024-01402

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes.

Hasenbein, T. P. ; Hoelzl, S. ; Smith, Z. D. ; Gerhardinger, C. ; Gonner, M. O. C. ; Aguilar-Pimentel, 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.DZNE* ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Meissner, A. ; Engelhardt, S. ; Rinn, J. L. ; Andergassen, D.

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-54673-5

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.

Keyword(s): Animals (MeSH) ; RNA, Long Noncoding: genetics (MeSH) ; RNA, Long Noncoding: metabolism (MeSH) ; Female (MeSH) ; Male (MeSH) ; Phenotype (MeSH) ; X Chromosome Inactivation: genetics (MeSH) ; Genes, X-Linked (MeSH) ; X Chromosome: genetics (MeSH) ; Genomic Imprinting (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Epigenesis, Genetic (MeSH) ; Alleles (MeSH) ; Mice, Inbred C57BL (MeSH) ; RNA, Long Noncoding

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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