Journal Article

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

de Wit, Elzo, Żylicz, Jan J., Gribnau, Joost, Galupa, Rafael, Higgs, Douglas R., Heard, Edith, Gard, Chris, Davies, James, Hughes, Jim R., Nora, Elphège P., Szempruch, Anthony James, Servant, Nicolas, Giorgetti, Luca, Guttman, Mitchell, Gentien, David, Lameiras, Sonia, Baulande, Sylvain, Picard, Christel, Zhan, Yinxiu, van Bemmel, Joke G.

2019

Overview

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. Swapping the Xist/Tsix transcriptional units and placing their promoters in each other’s topologically associating domain shows that the topological partitioning of the X-inactivation center is critical to ensure proper X inactivation during development.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/32 / 45/100 / 45/41 / 45/91 / 631/208/177 / 631/208/191 / 631/208/200 / 631/532 / 64/60 / Agriculture / Analysis / Animal Genetics and Genomics / Animals / Antisense RNA / Architectural engineering / Architecture / Binding sites / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Differentiation - genetics / Chromosomes / Cloning / CRISPR / Deactivation / Domains / Ectopic Gene Expression / Embryonic Stem Cells - cytology / Embryonic Stem Cells - metabolism / Female / Females / Gene expression / Gene Expression Regulation, Developmental / Gene Function / Gene regulation / Gene Silencing / Genetic aspects / Genetic Loci / Genetic regulation / Genetic transcription / Genomes / Growth / Human Genetics / Inactivation / Inversions / Landscape architecture / Life Sciences / Male / Mammals / Mice / Models, Biological / Pluripotency / Promoter Regions, Genetic / RNA, Long Noncoding - genetics / Sequence Inversion / Stem cells / Transcription / Transcription, Genetic / X Chromosome Inactivation