Dosage Compensation, the X-Factor Unveiled

Many animal species employ sex chromosomes to determine sex and start gender specific gene expression programs. In mammals female cells have two X chromosomes, whereas male cells carry an X and Y chromosome. The Y is a small chromosome with not more than 70 coding genes, in contrast to the X chromosome that harbours more than 1000 genes. As a consequence, expression of X linked genes will potentially be two-fold higher in female compared to male cells. But is this detrimental? Several examples indicate the importance of gene dosage. For instance one additional small chromosome 21 leads to Down syndrome, and children with other trisomies are not even born. Therefore, intricate mechanisms are installed to equalize the dosage of X-linked genes between male and female cells. In mammals this involves upregulation of X-linked genes, and inactivation of one X chromosome in every female somatic cell. X chromosome inactivation (XCI) is regulated by the X-linked X inactivation center (Xic). This Xic covers a region of ~800kb, and harbors a plethora of long non-coding RNA genes involved in XCI. Located within the Xic, Xist plays a crucial role in XCI. Xist RNA accumulates in cis, thereby recruiting silencing complexes that render the X inactive. One key intriguing question in XCI is how a cell determines the number of X chromosomes and initiates XCI. Our work and that of others has indicated that this process is directed by X-linked activators and autosomaly encoded inhibitors of XCI. In my seminar I will discuss our new insights in the interplay of these activators and inhibitors in the counting and feedback mechanisms required to maintain one active X chromosome in female cells.