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Proc Natl Acad Sci U S A. 2008 November 4; 105(44): 17055–17060.
doi: 10.1073/pnas.0807765105.
PMCID: PMC2579377
Genetics
Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus
Nan Liab and Laura Carrela1
aDepartment of Biochemistry and Molecular Biology and
bIntercollege Graduate Program in Genetics, Pennsylvania State College of Medicine, Hershey, PA 17033
1To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, Pennsylvania State College of Medicine, Hershey Medical Center, C5757, 500 University Drive, Hershey, PA 17033., E-mail: lcarrel/at/psu.edu
Edited by Stanley M. Gartler, University of Washington, Seattle, WA, and approved September 23, 2008
Author contributions: N.L. and L.C. designed research; N.L. and L.C. performed research; N.L. and L.C. analyzed data; and N.L. and L.C. wrote the paper.
Received August 8, 2008.
Abstract
Although most genes on one X chromosome in mammalian females are silenced by X inactivation, some “escape” X inactivation and are expressed from both active and inactive Xs. How these escape genes are transcribed from a largely inactivated chromosome is not fully understood, but underlying genomic sequences are likely involved. We developed a transgene approach to ask whether an escape locus is autonomous or is instead influenced by X chromosome location. Two BACs carrying the mouse Jarid1c gene and adjacent X-inactivated transcripts were randomly integrated into mouse XX embryonic stem cells. Four lines with single-copy, X-linked transgenes were identified, and each was inserted into regions that are normally X-inactivated. As expected for genes that are normally subject to X inactivation, transgene transcripts Tspyl2 and Iqsec2 were X-inactivated. However, allelic expression and RNA/DNA FISH indicate that transgenic Jarid1c escapes X inactivation. Therefore, transgenes at 4 different X locations recapitulate endogenous inactive X expression patterns. We conclude that escape from X inactivation is an intrinsic feature of the Jarid1c locus and functionally delimit this escape domain to the 112-kb maximum overlap of the BACs tested. Additionally, although extensive chromatin differences normally distinguish active and inactive loci, unmodified BACs direct proper inactive X expression patterns, establishing that primary DNA sequence alone, in a chromosome position-independent manner, is sufficient to determine X chromosome inactivation status. This transgene approach will enable further dissection of key elements of escape domains and allow rigorous testing of specific genomic sequences on inactive X expression.
Keywords: epigenetics, dosage compensation, transgene