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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.

Original publication

DOI

10.1038/s41588-019-0412-0

Type

Journal article

Journal

Nat Genet

Publication Date

06/2019

Volume

51

Pages

1024 - 1034

Keywords

Animals, Cell Differentiation, Ectopic Gene Expression, Embryonic Stem Cells, Female, Gene Expression Regulation, Developmental, Gene Silencing, Genetic Loci, Male, Mice, Models, Biological, Promoter Regions, Genetic, RNA, Long Noncoding, Sequence Inversion, Transcription, Genetic, X Chromosome Inactivation