TY  - JOUR
AU  - Hasenbein, Tim P
AU  - Hoelzl, Sarah
AU  - Smith, Zachary D
AU  - Gerhardinger, Chiara
AU  - Gonner, Marion O C
AU  - Aguilar-Pimentel, Antonio
AU  - Amarie, Oana V
AU  - Becker, Lore
AU  - Calzada-Wack, Julia
AU  - Dragano, Nathalia R V
AU  - da Silva-Buttkus, Patricia
AU  - Garrett, Lillian
AU  - Hölter, Sabine M
AU  - Kraiger, Markus
AU  - Östereicher, Manuela A
AU  - Rathkolb, Birgit
AU  - Sanz-Moreno, Adrián
AU  - Spielmann, Nadine
AU  - Wurst, Wolfgang
AU  - Gailus-Durner, Valerie
AU  - Fuchs, Helmut
AU  - Hrabě de Angelis, Martin
AU  - Meissner, Alexander
AU  - Engelhardt, Stefan
AU  - Rinn, John L
AU  - Andergassen, Daniel
TI  - X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2024-01402
SP  - 10631
PY  - 2024
AB  - 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.
KW  - Animals
KW  - RNA, Long Noncoding: genetics
KW  - RNA, Long Noncoding: metabolism
KW  - Female
KW  - Male
KW  - Phenotype
KW  - X Chromosome Inactivation: genetics
KW  - Genes, X-Linked
KW  - X Chromosome: genetics
KW  - Genomic Imprinting
KW  - Mice
KW  - Mice, Knockout
KW  - Epigenesis, Genetic
KW  - Alleles
KW  - Mice, Inbred C57BL
KW  - RNA, Long Noncoding (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39638999
C2  - pmc:PMC11621363
DO  - DOI:10.1038/s41467-024-54673-5
UR  - https://pub.dzne.de/record/273928
ER  -