Epigenetic Methylation Station

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X-Chromosome Inactivation

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The X chromosome is a sex chromosome found in humans, fruit flies and certain other animals where the male is the heterogametic sex. In the XY set of sex chromosomes, the female has two X chromosomes and the male has only one, and usually also a Y chromosome. In female mammalian embryos, X chromosome inactivation occurs. X chromosome inactivation is an early random inactivation of the genes on one of the X chromosomes, leading to mosaicism for functions coded by heterozygous X-linked genes. This dosage compensation of X-linked genes is achieved by transcriptional silencing of one of the two X chromosomes during early development (Avner and Heard, 2001).

The initial events in X inactivation are under the control of a key regulator, the X-chromosome inactivation centre ( Xic ). Xic is an approximately 1 Mb region that contains numerous elements thought to have a role in X inactivation and at least four genes (Heard et al., 1997). One particular gene, the X inactive-specific transcript ( Xist ) gene, encodes for a large non-coding RNA that is relatively poorly conserved. Xist has been shown to contribute to Xic function and is required for X inactivation (Avner and Heard, 2001). Other elements that lie within the Xic are candidate involved in the control of Xist expression, or for mechanisms of counting and choice (Courtier et al., 1995; Lee et al., 1999).

During random X inactivation, the coating of the presumptive inactive X by Xist occurs initially. Silencing of X-linked genes and replication asynchrony follow rapidly. Subsequently, global histone methylation, the accumulation of a novel histone variant (macroH2A) and methylation of the inactive X, function as the maintenance mechanisms that allow for X inactivation (Mermoud et al., 1999; Sado et al., 2000).

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