摘要：

In mammals, gene dosage of X-chromosomal genes is equalized between the sexes by random inactivation of either one of the two X chromosomes in female cells. X chromosome inactivation (XCI) is mediated by cis-accumulation of X-encoded Xist RNA on the inactive X chromosome. We identified the X-encoded E3-ubiquitin ligase RNF12 as a crucial activator of the XCI process, and discovered that RNF12 catalyzes the dose-dependent breakdown of REX1, which acts as a repressor of Xist. Only in female XX cells the concentration of RNF12 exceeds a threshold level for initiation of XCI. Recently, we analyzed heterozygous Rnf12 mutant mice and observed that XCI is compromised, resulting in a high percentage of cells showing expression of alleles from both X chromosomes. This intriguing finding suggests that XCI is dispensable, at least in a chimaeric environment where cells with two active X chromosomes can interact with cells which have properly inactivated one X chromosome. Here, we propose studies aimed at a better understanding of the XCI phenotype in Rnf12 heterozygous mice. This includes a more detailed evaluation of the question to what extent maintenance of XCI is, or is not, a lifelong requirement for female cells, tissues and whole animals, in mice. In addition, we aim to establish the role of RNF12 in human XCI. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation and treatment of X-linked diseases that are affected by XCI.

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