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

Daniel Andergassen,Jordan P Lewandowski,Alexander Meissner,John L Rinn,Chiara Gerhardinger,Zachary D Smith

doi:10.7554/elife.47214

Abstract

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.

Highlights

In female mammals, one of the two X chromosomes is inactivated to compensate for gene dosage between males and females (Lyon, 1961), a process termed X-chromosome inactivation (XCI)
The Firre and Dxz4 loci provide the platform for the formation of the X chromosome mega-structures and have been extensively studied in cell lines modeling random XCI (Rao et al, 2014; Horakova et al, 2012; Deng et al, 2015; Giorgetti et al, 2016; Bonora et al, 2018; Froberg et al, 2018; Darrow et al, 2016; Barutcu et al, 2018)
In agreement with previous in vitro studies, we find that the loss of these loci in vivo does not affect random XCI

Summary

Introduction

One of the two X chromosomes is inactivated to compensate for gene dosage between males and females (Lyon, 1961), a process termed X-chromosome inactivation (XCI). While the Xp remains silenced in extra-embryonic lineages (Takagi and Sasaki, 1975), it is reactivated in the embryo during implantation, followed by random XCI (Mak et al, 2004). After this decision has been made, the inactive X (Xi) chromosome is epigenetically maintained throughout cell division as a compact chromatin structure known as the ‘Barr body’ (Barr and Bertram, 1949). Recent studies in human and mouse cell line models of random XCI, found that deletion of these elements have minimal impact on X chromosome biology beyond the loss of these structures, though the phenotypic consequences of their deletion throughout mammalian

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Conclusion