Refining the genomic determinants underlying escape from X-chromosome inactivation

• Published in: NAR genomics and bioinformatics Vol. 5; no. 2; p. lqad052
• Main Authors: Peeters, Samantha, Leung, Tiffany, Fornes, Oriol, Farkas, Rachelle A, Wasserman, Wyeth W, Brown, Carolyn J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2023
• Subjects: Editor's Choice; Gene expression; Gene silencing; Genes; Phenotypes; Sex differences; Transcription factors; Transgenes; Transgenic mice; X chromosomes; X-chromosome inactivation
• ISSN: 2631-9268; 2631-9268
• DOI: 10.1093/nargab/lqad052

Abstract X-chromosome inactivation (XCI) epigenetically silences one X chromosome in every cell in female mammals. Although the majority of X-linked genes are silenced, in humans 20% or more are able to escape inactivation and continue to be expressed. Such escape genes are important contributors to sex differences in gene expression, and may impact the phenotypes of X aneuploidies; yet the mechanisms regulating escape from XCI are not understood. We have performed an enrichment analysis of transcription factor binding on the X chromosome, providing new evidence for enriched factors at the transcription start sites of escape genes. The top escape-enriched transcription factors were detected at the RPS4X promoter, a well-described human escape gene previously demonstrated to escape from XCI in a transgenic mouse model. Using a cell line model system that allows for targeted integration and inactivation of transgenes on the mouse X chromosome, we further assessed combinations of RPS4X promoter and genic elements for their ability to drive escape from XCI. We identified a small transgenic construct of only 6 kb capable of robust escape from XCI, establishing that gene-proximal elements are sufficient to permit escape, and highlighting the additive effect of multiple elements that work together in a context-specific fashion.