The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Joke G. van Bemmel
  • Rafael Galupa
  • Chris Gard
  • Nicolas Servant
  • Christel Picard
  • James Davies
  • Anthony James Szempruch
  • Yinxiu Zhan
  • Jan J. Żylicz
  • Elphège P. Nora
  • Sonia Lameiras
  • Elzo de Wit
  • David Gentien
  • Sylvain Baulande
  • Luca Giorgetti
  • Mitchell Guttman
  • Jim R. Hughes
  • Douglas R. Higgs
  • Joost Gribnau
  • Edith Heard

The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other’s TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind51
Udgave nummer6
Sider (fra-til)1024-1034
Antal sider11
ISSN1061-4036
DOI
StatusUdgivet - 1 jun. 2019
Eksternt udgivetJa

Bibliografisk note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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