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

Nature Genetics volume 51, pages 1024–1034 (2019)Cite this article

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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.

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Fig. 1: Genomic inversion of the Xist/Tsix loci switches their promoters into each other’s original TADs.
Fig. 2: Genomic inversion of the Xist/Tsix loci along with Xite and Jpx leads to topological changes within the Xic.
Fig. 3: Xite structural element is important for TAD boundary position and insulation.
Fig. 4: Xist/Tsix inversions lead to ectopic Xist expression, Xist RNA coating and X-linked gene silencing in male mESCs.
Fig. 5: Xist/Tsix inversions affect the initiation of XCI and the expression dynamics of Xist and Tsix during differentiation of female mESCs.

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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.

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Acknowledgements

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.

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Author notes

  1. Joke G. van Bemmel

    Present address: Gladstone Institute of Cardiovascular Diseases, San Francisco, CA, USA

  2. Rafael Galupa

    Present address: European Molecular Biology Laboratory, Heidelberg, Germany

  3. These authors contributed equally: Joke G. van Bemmel, Rafael Galupa.

Authors and Affiliations

  1. Institut Curie, CNRS UMR3215, INSERM U934, Paris, France

    Joke G. van Bemmel, Rafael Galupa, Chris Gard, Christel Picard, Jan J. Żylicz & Edith Heard

  2. Department of Developmental Biology, Erasmus Medical Center Rotterdam (EMC), Rotterdam, the Netherlands

    Joke G. van Bemmel & Joost Gribnau

  3. Institut Curie, PSL Research University, INSERM, U900, Paris, France

    Nicolas Servant

  4. MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France

    Nicolas Servant

  5. Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    James Davies, Jim R. Hughes & Douglas R. Higgs

  6. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Anthony James Szempruch & Mitchell Guttman

  7. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    Yinxiu Zhan & Luca Giorgetti

  8. University of Basel, Basel, Switzerland

    Yinxiu Zhan

  9. University of Cambridge, Department of Physiology, Development and Neuroscience, Cambridge, UK

    Jan J. Żylicz

  10. Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA

    Elphège P. Nora

  11. Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France

    Sonia Lameiras & Sylvain Baulande

  12. Oncode Institute and Division of Gene Regulation, the Netherlands Cancer Institute, Amsterdam, the Netherlands

    Elzo de Wit

  13. Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France

    David Gentien

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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.

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Correspondence to Joke G. van Bemmel or Edith Heard.

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van Bemmel, J.G., Galupa, R., Gard, C. et al. The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist. Nat Genet 51, 1024–1034 (2019). https://doi.org/10.1038/s41588-019-0412-0

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