A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary

Rafael Galupa; Elphège Pierre Nora; Rebecca Worsley-Hunt; Christel Picard; Chris Gard; Joke Gerarda van Bemmel; Nicolas Servant; Yinxiu Zhan; Fatima El Marjou; Colin Johanneau; Patricia Diabangouaya; Agnès Le Saux; Sonia Lameiras; Juliana Pipoli da Fonseca; Friedemann Loos; Joost Gribnau; Sylvain Baulande; Uwe Ohler; Luca Giorgetti; Edith Heard

doi:10.1016/j.molcel.2019.10.030

A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary

Mol Cell. 2020 Jan 16;77(2):352-367.e8. doi: 10.1016/j.molcel.2019.10.030. Epub 2019 Nov 20.

Authors

Rafael Galupa¹, Elphège Pierre Nora¹, Rebecca Worsley-Hunt², Christel Picard¹, Chris Gard¹, Joke Gerarda van Bemmel¹, Nicolas Servant³, Yinxiu Zhan⁴, Fatima El Marjou⁵, Colin Johanneau⁵, Patricia Diabangouaya¹, Agnès Le Saux¹, Sonia Lameiras⁶, Juliana Pipoli da Fonseca⁶, Friedemann Loos⁷, Joost Gribnau⁷, Sylvain Baulande⁶, Uwe Ohler⁸, Luca Giorgetti⁹, Edith Heard¹⁰

Affiliations

¹ Mammalian Developmental Epigenetics Group, Genetics and Developmental Biology Unit, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.
² Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
³ 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.
⁴ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; University of Basel, Basel, Switzerland.
⁵ Transgenesis Facility, Institut Curie, Paris, France.
⁶ Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie, Paris, France.
⁷ Department of Developmental Biology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
⁸ 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.
⁹ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
¹⁰ 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. Electronic address: edith.heard@embl.org.

Abstract

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.

Keywords: 5C; Linx; TADs; X-inactivation; Xist; cis-regulatory landscape; enhancer; gene regulation; noncoding RNA; silencer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Conserved Sequence / genetics*
Enhancer Elements, Genetic / genetics
Mice
Promoter Regions, Genetic / genetics
RNA, Antisense / genetics
RNA, Long Noncoding / genetics*
Silencer Elements, Transcriptional / genetics
Transcription, Genetic / genetics
X Chromosome / genetics*

Substances

RNA, Antisense
RNA, Long Noncoding