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Species-specific regulation of XIST by the JPX/FTX orthologs

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Rosspopoff, Olga 
Cazottes, Emmanuel 
Huret, Christophe 
Loda, Agnese 
Collier, Amanda J 


X chromosome inactivation (XCI) is an essential process, yet it initiates with remarkable diversity in various mammalian species. XIST, the main trigger of XCI, is controlled in the mouse by an interplay of lncRNA genes (LRGs), some of which evolved concomitantly to XIST and have orthologues across all placental mammals. Here, we addressed the functional conservation of human orthologues of two such LRGs, FTX and JPX. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in matched human and mouse pluripotent stem- or differentiated post-XCI cells, we demonstrate major functional differences for these orthologues between species, independently of primary sequence conservation. While the function of FTX is not conserved in humans, JPX stands as a major regulator of XIST expression in both species. However, we show that different entities of JPX control the production of XIST at various steps depending on the species. Altogether, our study highlights the functional versatility of LRGs across evolution, and reveals that functional conservation of orthologous LRGs may involve diversified mechanisms of action. These findings represent a striking example of how the evolvability of LRGs can provide adaptative flexibility to constrained gene regulatory networks.


Acknowledgements: We thank lab members for critical evaluation of the work leading to this publication. We also thank Antonin Morillon, Pierre-Antoine Defossez, Claire Francastel, Jonathan Weitzman and Céline Morey for critical reading of the manuscript. We thank the Epigenomic, the Microscopy, the Vectorology and the BIBS Platforms, all hosted in UMR7216 Epigenetic and Cell Fate, for technical advices and access to instruments. We thank Laura Villacorta from EMBL GeneCore for NGS and Nicolas Servant for the help in the analysis of Capture Hi-C data. We acknowledge the ImagoSeine core facility of the Institut Jacques Monod, member of the France BioImaging (ANR-10-INBS-04) and the support of the Region Île-de-France (E539).

Funder: Ligue Nationale contre le Cancer

Funder: French Ministry of Education and Research

Funder: French Medical Research Foundation


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Nucleic Acids Research

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Oxford University Press
European Research Council (101020423)
European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082)
Agence Nationale pour la Recherche (ANR-14-CE10-0017)
LabEx ‘Who Am I?’ (ANR-11-LABX-0071)
Université de Paris IdEx (ANR-18-IDEX-0001)
Biotechnology and Biological Sciences Research Council (BB/M022285/1, BB/P013406/1)
Medical Research Council (MR/J003808/1)
European Research Council (XPRESS — AdG671027)
European Union Marie Skłodowska-Curie (IF-838408)