A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary.,Molecular Cell

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A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-20 , DOI: 10.1016/j.molcel.2019.10.030
Rafael Galupa ₁ , Elphège Pierre Nora ₁ , Rebecca Worsley-Hunt ₂ , Christel Picard ₁ , Chris Gard ₁ , Joke Gerarda van Bemmel ₁ , Nicolas Servant ₃ , Yinxiu Zhan ₄ , Fatima El Marjou ₅ , Colin Johanneau ₅ , Patricia Diabangouaya ₁ , Agnès Le Saux ₁ , Sonia Lameiras ₆ , Juliana Pipoli da Fonseca ₆ , Friedemann Loos ₇ , Joost Gribnau ₇ , Sylvain Baulande ₆ , Uwe Ohler ₈ , Luca Giorgetti ₉ , Edith Heard ₁₀

Affiliation

Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.
Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Bioinformatics, Biostatistics, Epidemiology and Computational Systems Unit, Institut Curie, PSL Research University, INSERM U900, Paris, France; MINES ParisTech, PSL Research University, Centre for Computational Biology (CBIO), Paris, France.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; University of Basel, Basel, Switzerland.
Transgenesis Facility, Institut Curie, Paris, France.
Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie, Paris, France.
Department of Developmental Biology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Biology, Humboldt University, Berlin, Germany.
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France; Collège de France, Paris, France.

cis-Regulatory communication is crucial in mammalian development and is thought to be restricted by the spatial partitioning of the genome in topologically associating domains (TADs). Here, we discovered that the Xist locus is regulated by sequences in the neighboring TAD. In particular, the promoter of the noncoding RNA Linx (LinxP) acts as a long-range silencer and influences the choice of X chromosome to be inactivated. This is independent of Linx transcription and independent of any effect on Tsix, the antisense regulator of Xist that shares the same TAD as Linx. Unlike Tsix, LinxP is well conserved across mammals, suggesting an ancestral mechanism for random monoallelic Xist regulation. When introduced in the same TAD as Xist, LinxP switches from a silencer to an enhancer. Our study uncovers an unsuspected regulatory axis for X chromosome inactivation and a class of cis-regulatory effects that may exploit TAD partitioning to modulate developmental decisions.

中文翻译：

保守的非编码基因座调节跨拓扑边界的随机单等位基因 Xist 表达。

顺式调控通讯在哺乳动物发育中至关重要，并且被认为受到拓扑关联域（TAD）中基因组空间划分的限制。在这里，我们发现 Xist 基因座受邻近 TAD 中的序列调控。特别是，非编码 RNA Linx (LinxP) 的启动子充当远程沉默子，影响 X 染色体失活的选择。这独立于 Linx 转录，也独立于对 Tsix 的任何影响，Tsix 是 Xist 的反义调节因子，与 Linx 具有相同的 TAD。与 Tsix 不同，LinxP 在哺乳动物中非常保守，这表明随机单等位基因 Xist 调节的祖先机制。当与 Xist 引入同一 TAD 时，LinxP 从消音器切换为增强器。我们的研究揭示了 X 染色体失活的一个意想不到的调节轴和一类可能利用 TAD 分配来调节发育决策的顺式调节效应。

更新日期：2019-11-21

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