The inactive X chromosome differs from the active X in a number of ways; some of these, such as allocyclic replication and altered histone acetylation, are associated with all types of epigenetic silencing, whereas others, such as DNA methylation, are of more restricted use. These features are acquired progressively by the inactive X after onset of initiation. Initiation of X-inactivation is controlled by the X-inactivation center (Xic) and influenced by the X chromosome controlling element (Xce), which causes primary nonrandom X-inactivation. Other examples of nonrandom X-inactivation are also presented in this review. The definition of a major role for Xist, a noncoding RNA, in X-inactivation has enabled investigation of the mechanism leading to establishment of the heterochromatinized X-chromosome and also of the interactions between X-inactivation and imprinting as well as between X-inactivation and developmental processes in the early embryo.
The initial differential treatment of the two X chromosomes during X-chromosome inactivation is controlled by the X-inactivation centre (Xic). This locus determines how many X chromosomes are present in a cell ('counting') and which X chromosome will be inactivated in female cells ('choice'). Critical control sequences in the Xic include the non-coding RNAs Xist and Tsix, and long-range chromatin elements. However, little is known about the process that ensures that X inactivation is triggered appropriately when more than one Xic is present in a cell. Using three-dimensional fluorescence in situ hybridization (FISH) analysis, we showed that the two Xics transiently colocalize, just before X inactivation, in differentiating female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, we demonstrated that Xic colocalization is linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, are required for the transient interaction of Xics. We propose that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.
Virulent strains of Shigellaflexneri invade HeLa cells with high efficiency. This crucial step in the pathogenic process is encoded by a 140-megadalton plasmid which induces phagocytosis of the bacteria by host cells. In this report we used pWR100, the virulence plasmid of S. flexneri serotype 5, and pHS4108, a 32-megadalton subclone of pWR100, to demonstrate that the plasmid is also responsible for rapid intracellular growth of the bacteria. The ability to replicate intracellularly was not correlated with induction of Shiga toxin. However, plasmid-mediated intracellular multiplication was strongly correlated with the ability of the bacteria to rapidly and efficiently lyse the phagocytic vacuole and replicate freely in the cytoplasm. Temperature-regulated plasmid-mediated contact hemolytic activity strongly correlated with both phagosomal membrane lysis and efficient intracellular multiplication. We propose this virulence plasmid-associated hemolysin to be an important factor in the invasion and proliferation of Shigella spp. in mammalian cells.
Structural analyses provide new insights into the folding of the A region of the Xist RNA, which plays a crucial role in X chromosome inactivation, and its mechanism of protein recruitment.
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