KNAW

Research

Activation of X-chromosome inactivation

Pagina-navigatie:


Update content


Title Activation of X-chromosome inactivation
Period 02 / 2010 - unknown
Status Current
Research number OND1325596
Data Supplier NWO

Abstract

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. Xist, Tsix and Xite are non-coding genes located in a small region on the X chromosome, which play a crucial role in X-chromosome inactivation (XCI). Xist RNA accumulates on the future inactive X chromosome and initiates silencing in cis. Tsix and Xite down-regulate Xist transcription, acting against XCI. In the initial phase of XCI, a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome. We found that this process is directed by a stochastic mechanism, in which each X chromosome has a specific probability to be inactivated. We also showed that the probability to initiate XCI is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of the XCI process. With a BAC screen we recently identified X-encoded RNF12 to be an activator of XCI. A heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells, confirming a prominent role of RNF12 in XCI. The remained presence of a small proportion of cells that do initiate XCI also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI, and to search for additional XCI-activators. Complementary to this, we will also attempt to determine the structure of Xist RNA and its RNA-protein complexes. In addition, we aim to determine the role of RNF12 and other XCI-activators 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 of X-linked diseases that are affected by XCI.

Related organisations

Related people

Project leader Prof.dr. J.H. Gribnau

Classification

D21400 Genetics
D21500 Histology, cell biology
D22600 Zoology

Go to page top
Go back to contents
Go back to site navigation