Genetic and pharmacological reactivation of the mammalian inactive X chromosome
Program in Gene Function and Expression
Bioinformatics | Cell Biology | Computational Biology | Genetics and Genomics | Integrative Biology
X-chromosome inactivation (XCI), the random transcriptional silencing of one X chromosome in somatic cells of female mammals, is a mechanism that ensures equal expression of X-linked genes in both sexes. XCI is initiated in cis by the noncoding Xist RNA, which coats the inactive X chromosome (Xi) from which it is produced. However, trans-acting factors that mediate XCI remain largely unknown. Here, we perform a large-scale RNA interference screen to identify trans-acting XCI factors (XCIFs) that comprise regulators of cell signaling and transcription, including the DNA methyltransferase, DNMT1. The expression pattern of the XCIFs explains the selective onset of XCI following differentiation. The XCIFs function, at least in part, by promoting expression and/or localization of Xist to the Xi. Surprisingly, we find that DNMT1, which is generally a transcriptional repressor, is an activator of Xist transcription. Small-molecule inhibitors of two of the XCIFs can reversibly reactivate the Xi, which has implications for treatment of Rett syndrome and other dominant X-linked diseases. A homozygous mouse knockout of one of the XCIFs, stanniocalcin 1 (STC1), has an expected XCI defect but surprisingly is phenotypically normal. Remarkably, X-linked genes are not overexpressed in female Stc1(-/-) mice, revealing the existence of a mechanism(s) that can compensate for a persistent XCI deficiency to regulate X-linked gene expression.
DOI of Published Version
Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12591-8. doi: 10.1073/pnas.141362011110.1073/pnas.1413620111. Epub 2014 Aug 18. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Bhatnagar S, Zhu X, Ou J, Lin L, Chamberlain L, Zhu LJ, Wajapeyee N, Green MR. (2014). Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Program in Gene Function and Expression Publications. https://doi.org/10.1073/pnas.141362011110.1073/pnas.1413620111. Retrieved from https://escholarship.umassmed.edu/pgfe_pp/265