CaltechAUTHORS
Published June 2019 | Version Accepted Version + Supplemental Material
Journal Article Open

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

Creators

  • 1. ROR icon Institute Curie
  • 2. ROR icon Erasmus MC
  • 3. ROR icon European Molecular Biology Laboratory
  • 4. ROR icon Inserm
  • 5. ROR icon Mines ParisTech
  • 6. ROR icon John Radcliffe Hospital
  • 7. ROR icon California Institute of Technology
  • 8. ROR icon University of Basel
  • 9. ROR icon University of Cambridge
  • 10. ROR icon Gladstone Institutes
  • 11. ROR icon Antoni van Leeuwenhoek Hospital

Abstract

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.

Additional Information

© 2019 Springer Nature Publishing AG. Received 04 March 2018; Accepted 04 April 2019; Published 27 May 2019. Data availability: Data have been deposited in the NCBI GEO under the accession number GSE111205. Reagents, cell lines and other data supporting the findings of this study are available from the corresponding author upon request. Code availability: Our custom pipeline for 5C data processing, 5C-Pro, is available at https://github.com/bioinfo-pf-curie/5C-Pro. Custom codes used in this study will be provided upon request. We would like to thank the Heard laboratory for their technical input and critical discussions; D. Noordermeer for critical discussion and advice on Capture-C data analysis and interpretation; A. Chow from the Guttman laboratory for RAP-DNA cell culture; members of the Bourc'his laboratory; C. Reyes and A. Rapinat from the Nanostring platform and J. M. Telenius, M. Oudelaar and D. Downes from the Hughes and Higgs laboratories. This work was supported by an ERC Advanced Investigator award (ERC-2014-AdG no. 671027), Labelisation La Ligue, FRM (grant no. DEI20151234398), ANR DoseX 2017, Labex DEEP (no. ANR-11-LBX-0044), part of the IDEX Idex PSL (no. ANR-10-IDEX-0001-02 PSL) and ABS4NGS (no. ANR-11-BINF-0001) to E.H.; NWO-ALW Rubicon (no. 825.13.002) and Veni (no. 863.15.016) fellowships to J.G.v.B.; Région Ile-de-France (DIM Biothérapies) and Fondation pour la Recherche Médicale (no. FDT20160435295) fellowships to R.G.; Sir Henry Wellcome Postdoctoral Fellowship (no. 201369/Z/16/Z) to J.J.Z.; MRC Clinician Scientist Fellowship (no. MR/R008108) to J.D.; Wellcome Trust Strategic Award (no. 106130/Z/14/Z) to J.R.H.; New York Stem Cell Foundation and California Institute of Technology funds to M.G. (M.G. is a New York Stem Cell Foundation—Robertson Investigator); Novartis Foundation and European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 759366 'BioMeTre') to L.G.; LabEx and EquipEx (nos. ANR-10-IDEX-0001-02 PSL, ANR-11-LBX-0044 and 'INCa-DGOS-4654' SIRIC11-002) to the Nanostring platform of Institut Curie; Equipex (no. ANR-10-EQPX-03), France Génomique Consortium from the Agence Nationale de la Recherche ('Investissements d'Avenir' program; no. ANR-10-INBS-09-08) and Canceropole Ile-de-France and by the SiRIC-Curie program—SiRIC grant (no. INCa-DGOS-4654) to the ICGex Next Generation Sequencing platform of the Institut Curie. Author Contributions: J.G.v.B., J.G. and E.H. conceived the study, with support from R.G., L.G. and E.P.N. J.G.v.B., N.S. (lead), R.G., A.J.S., Y.Z., E.d.W. and L.G. (equal) conducted the formal analysis. J.G.v.B and R.G. led the investigation. C.G., A.J.S., C.P., E.P.N., J.J.Z. and S.L. supported the investigation. J.D., Y.Z., L.G., J.D., J.R.H. and D.R.H. provided resources. J.G.v.B. and E.H. wrote and prepared the original draft, with support from E.P.N., R.G. and C.G and input from all authors. R.G. and E.H. led the revision and editing of the article, with support from J.G.v.B. J.G.v.B. and R.G. provided data visualization. J.G.v.B., R.G. and E.H. supervised the study, with support from J.D., D.G., S.B., M.G., J.R.H., D.R.H. and J.G. The funding was acquired by E.H., J.G.v.B. and J.G. The authors declare no competing interests.

Attached Files

Accepted Version - emss-82531.pdf

Supplemental Material - 41588_2019_412_MOESM1_ESM.pdf

Supplemental Material - 41588_2019_412_MOESM2_ESM.pdf

Supplemental Material - 41588_2019_412_MOESM3_ESM.zip

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Additional details

Identifiers

PMCID
PMC6551226
Eprint ID
96025
DOI
10.1038/s41588-019-0412-0
Resolver ID
CaltechAUTHORS:20190603-084109257

Related works

Describes
10.1038/s41588-019-0412-0 (DOI)

Funding

European Research Council (ERC)
671027
Labelisation La Ligue
DEI20151234398
Agence Nationale pour la Recherche (ANR)
DoseX 2017
Agence Nationale pour la Recherche (ANR)
ANR-11-LBX-0044
Agence Nationale pour la Recherche (ANR)
ANR-10-IDEX-0001-02 PSL
Agence Nationale pour la Recherche (ANR)
ANR-11-BINF-0001
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
825.13.002
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)
863.15.016
Région Ile-de-France
Fondation pour la Recherche Médicale
FDT20160435295
Wellcome Trust
201369/Z/16/Z
Medical Research Council (UK)
MR/R008108
Wellcome Trust
106130/Z/14/Z
New York Stem Cell Foundation
Caltech
Novartis Foundation
European Research Council (ERC)
759366
Site de Recherche Intégrée sur le Cancer–Curie
SIRIC11-002
Nanostring platform of Institut Curie
Agence Nationale pour la Recherche (ANR)
ANR-10-EQPX-03
France Génomique Consortium
Agence Nationale pour la Recherche (ANR)
ANR-10-INBS-09-08
Canceropole Ile-de-France

Dates

Created
2019-06-03
Created from EPrint's datestamp field
Updated
2022-02-16
Created from EPrint's last_modified field