ABSTRACT
One X chromosome, selected at random, is silenced in each female mammalian cell. Xist encodes a noncoding RNA that influences the probability that the cis-linked X chromosome will be silenced. We found that the A-repeat, a highly conserved element within Xist, is required for the accumulation of spliced Xist RNA. In addition, the A-repeat is necessary for X-inactivation to occur randomly. In combination, our data suggest that normal Xist RNA processing is important in the regulation of random X-inactivation. We propose that modulation of Xist RNA processing may be part of the stochastic process that determines which X chromosome will be inactivated.
Subject(s)
Nuclear Proteins/metabolism , RNA Processing, Post-Transcriptional , RNA, Untranslated/genetics , RNA-Binding Proteins/metabolism , Repetitive Sequences, Nucleic Acid/genetics , X Chromosome Inactivation/genetics , Alleles , Animals , Base Sequence , Chromosomes, Mammalian/metabolism , Female , HeLa Cells , Histones/metabolism , Humans , Male , Mice , Models, Biological , Molecular Sequence Data , Nucleic Acid Conformation , Protein Binding , Protein Processing, Post-Translational , RNA, Long Noncoding , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Untranslated/chemistry , Sequence Deletion/genetics , Serine-Arginine Splicing FactorsABSTRACT
In female mammals, one X chromosome is transcriptionally silenced to achieve dosage compensation between XX females and XY males. This process, known as X-inactivation, occurs early in development, such that one X chromosome is silenced in every cell. Once X-inactivation has occurred, the inactive X chromosome is marked by a unique set of epigenetic features that distinguishes it from the active X chromosome and autosomes. These modifications appear sequentially during the transition from a transcriptionally active to an inactive state and, once established, act redundantly to maintain transcriptional silencing. In this review, we survey the unique epigenetic features that characterize the inactive X chromosome, describe the mechanisms by which these marks are established and maintained, and discuss how each contributes to silencing the inactive X chromosome.
