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.


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*


  • RNA, Antisense
  • RNA, Long Noncoding