期刊
NATURE GENETICS
卷 51, 期 6, 页码 1024-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-019-0412-0
关键词
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资金
- ERC Advanced Investigator award [671027]
- Labelisation La Ligue, FRM [DEI20151234398]
- ANR DoseX 2017, Labex DEEP [ANR-11-LBX-0044]
- IDEX Idex PSL [ANR-10-IDEX-0001-02 PSL]
- ABS4NGS [ANR-11-BINF-0001]
- NWO-ALW [825.13.002, 863.15.016]
- Region Ile-de-France
- Fondation pour la Recherche Medicale [FDT20160435295]
- Sir Henry Wellcome Postdoctoral Fellowship [201369/Z/16/Z]
- MRC Clinician Scientist Fellowship [MR/R008108]
- Wellcome Trust Strategic Award [106130/Z/14/Z]
- New York Stem Cell Foundation and California Institute of Technology funds
- Novartis Foundation
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [759366]
- LabEx and EquipEx [ANR-11-LBX-0044, ANR-10-IDEX-0001-02 PSL, 'INCa-DGOS-4654' SIRIC11-002]
- Equipex [ANR-10-EQPX-03]
- Agence Nationale de la Recherche [ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program-SiRIC grant [INCa-DGOS-4654]
- Wellcome Trust [201369/Z/16/Z] Funding Source: Wellcome Trust
- European Research Council (ERC) [671027, 759366] Funding Source: European Research Council (ERC)
- MRC [MC_U137961145, G1000801, MC_UU_00016/4, MC_UU_12009/4, MR/N00969X/1, MR/R008108/1, MC_U137961144, MC_PC_15065, MC_UU_12009/15, MC_UU_00016/14] Funding Source: UKRI
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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