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Recent insights into the regulation of X-chromosome inactivation

Authors Valencia K, Wutz A

Received 3 February 2015

Accepted for publication 5 March 2015

Published 14 May 2015 Volume 2015:5 Pages 227—238

DOI https://doi.org/10.2147/AGG.S60399

Checked for plagiarism Yes

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Editor who approved publication: Dr John Martignetti


Karmele Valencia, Anton Wutz

Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland

Abstract: X-chromosome inactivation (XCI) is the mechanism by which mammals compensate gene dosage differences between males and females. XCI is required for female development and has implications for human disease. As a result, a single X chromosome is transcriptionally active in both male and female cells. Functional hemizygosity of the X chromosomes greatly predisposes to phenotypic consequences of mutations. In females, X chromosomes are randomly chosen to become inactivated leading to a mosaic pattern of cells expressing genes from either chromosome. This facilitates the masking of phenotypic consequences of heterozygous X-linked mutations. Skewing of XCI in favor of one chromosome can result in increased severity of disease symptoms, if the X chromosome with a gene mutation remains preferentially active. In addition, phenotypic masking of X-linked mutations is not always observed. Rett syndrome represents a paradigm of this statement. Dosage compensation can also mask some aspects of sex chromosome aneuploidies. X-chromosome aneuploidies include Klinefelter, Turner, and X-trisomy syndromes. In all these cases, a single active X chromosome is present. However, in those cases with two or more X chromosomes, some genes from the inactivated X chromosome escape from XCI becoming active. Therefore, dose imbalances of escape genes cause pathologies. Defects in the structure and silencing of the inactive X chromosome are further observed in human pluripotent stem cells and in certain tumors. Taken together, these findings suggest that aspects of XCI are relevant for a large number of human diseases. Here we review basic and clinical research on XCI with the aim of illustrating connections and highlighting opportunities for future investigation.

Keywords: XCI, X-linked diseases, sex chromosome aneuploidies, iPSCs, cancer

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