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Distal and proximal cis-regulatory elements sense X chromosome dosage and developmental state at the Xist locus

MPS-Authors
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Gjaltema,  Rutger
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Schwämmle,  Till
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kautz,  Pauline
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Lustig,  Liat Ravid
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

Brandenburg,  Lennart
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Dunkel,  Ilona
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vechiatto,  Carolina
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

Ntini,  Evgenia
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mutzel,  Verena
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

Schmiedel,  Vera
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Schulz,  Edda G.
Systems Epigenetics (Edda G. Schulz), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Gjaltema et al_2021.pdf
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Citation

Gjaltema, R., Schwämmle, T., Kautz, P., Robson, M., Schöpflin, R., Lustig, L. R., et al. (2022). Distal and proximal cis-regulatory elements sense X chromosome dosage and developmental state at the Xist locus. Molecular Cell, 82, 1-19. doi:10.1016/j.molcel.2021.11.023.


Cite as: http://hdl.handle.net/21.11116/0000-0009-B883-3
Abstract
Developmental genes such as Xist, which initiates X chromosome inactivation, are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatiotemporal expression patterns. Xist integrates information on X chromosome dosage and developmental stage to trigger X inactivation in the epiblast specifically in female embryos. Through a pooled CRISPR screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist at the onset of random X inactivation. Chromatin profiling reveals that X-dosage controls the promoter-proximal region, while differentiation cues activate several distal enhancers. The strongest distal element lies in an enhancer cluster associated with a previously unannotated Xist-enhancing regulatory transcript, which we named Xert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specific Xist upregulation at the correct developmental time. With this study, we start to disentangle how multiple, functionally distinct regulatory elements interact to generate complex expression patterns in mammals.