Activation of X Chromosome Inactivation

In mammals, males are the heterogametic sex having an X chromosome and a Y chromosome whereas females have two X chromosomes. Despite originating from an ancient homologous autosomal pair, the X and Y chromosome now differ greatly in size and gene content after ~180 MY of evolution. The X chromosome retained over 1000 genes, whereas the Y chromosome degenerated over time and only contains about a hundred genes mainly involved in male spermatogenesis. Females have two X chromosomes and thus double the amount of X-encoded genes as compared to males which creates an imbalance of X-encoded genes between males and females. Mammals achieve dosage compensation of this imbalance of X-encoded genes by inactivating one of the two X chromosomes in female cells by a process called X chromosome inactivation (XCI). XCI is a stochastic process in which each X chromosome has an equal probability to be inactivated. Even though XCI is stochastic, it is a tightly regulated process to obtain one active X chromosome per diploid genome. Regulation of XCI is achieved by the X inactivation center (Xic), located on the X chromosome, which harbors all the necessary elements for XCI to occur. These elements are regulated by XCI activators and inhibitors. The aim of this thesis is to gain more insight into the molecular m

Xist and Tsix transcription dynamics is regulated by the X-to-autosome ratio and semistable transcriptional states

In female mammals, X chromosome inactivation (XCI) is a key process in the control of gene dosage compensation between Xlinked genes and autosomes. Xist and Tsix, two overlapping antisense-transcribed noncoding genes, are central elements of the X inactivation center (Xic) regulating XCI. Xist upregulation results in the coating of the entire X chromosome by Xist RNA in cis, whereas Tsix transcription acts as a negative regulator of Xist. Here, we generated Xist and Tsix reporter mouse embryonic stem (ES) cell lines to study the genetic and dynamic regulation of these genes upon differentiation. Our results revealed mutually antagonistic roles for Tsix on Xist and vice versa and indicate the presence of semistable transcriptional states of the Xic locus predicting the outcome of XCI. These transcriptional states are instructed by the X-t

Fitting the Puzzle Pieces: The Bigger Picture of XCI

X chromosome inactivation (XCI) is a mammalian-specific process initiated in all female cells, leading to one inactivated X chromosome. The robust nature of XCI, and the complex mechanisms involved in directing this process, makes XCI an important model system to study all aspects of gene regulation. XCI is divided into distinct phases: initiation, establishment, and maintenance of the inactive X (Xi). Recent studies shed important new light on the mechanisms directing all three phases of XCI. These findings include new regulatory pathways in XCI initiation, and the identification of a plethora of new factors involved in establishing and maintaining the Xi. In this review, we will highlight and discuss these new findings in the bigger picture of XCI