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Recent evidence has determined that the conserved X chromosome mega-structures controlled by the  Firre  and  Dxz4  loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by generating mice carrying a single or double deletion of  Firre  and  Dxz4 . We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and  Firre  locus-dependent gene sets. The largest transcriptional effect was observed in all strains lacking the  Firre  locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.

In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation