In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation
In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation
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DOI：
10.7554/elife.47214
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发表时间：
2019-11-18
期刊：
影响因子：
7.7
通讯作者：
Rinn, John L.
中科院分区：
文献类型：
--
作者：
Andergassen, Daniel;Smith, Zachary D.;Rinn, John L.
最近的证据已经确定，由Firre和Dxz4基因座控制的保守的X染色体巨型结构对于细胞系中的X染色体失活（XCI）是不需要的。在这里，我们通过产生携带Firre和Dxz4的单或双缺失的小鼠来检查这些基因座的体内贡献。我们发现这些突变体是可行的，可育的，并显示没有缺陷的随机或印迹XCI。然而，这些元件的缺乏导致常染色体上的许多失调基因以器官特异性的方式表达。通过比较单缺失和双缺失之间的失调基因，我们确定了超环，megadomain和Firre位点依赖的基因集。在缺乏Firre基因座的所有菌株中观察到最大的转录效应，表明该基因座是这些常染色体表达特征的主要驱动因素。总的来说，这些发现表明，这些X连锁基因座参与常染色体基因调控，而不是XCI生物学。
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.