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Molecular mechanisms controlling X chromosome inactivation

Final Report Summary - ACTIVATION OF XCI (Molecular mechanisms controlling X chromosome inactivation)

All biological differences between women and men originate from the sex chromosomes. Some 160 million years ago, the X and Y chromosomes were very similar, but since then the Y chromosome has lost most of its genes, whereas the present X chromosome contains more than 1000 genes. Hence, the dosage of X-encoded genes needs to be equalized between female (XX) and male (XY) cells. This is achieved by random inactivation of one of the X chromosomes in female embryonic cells. A central key in this X chromosome inactivation (XCI) process is the X-encoded long non-coding RNA Xist. Following up-regulation from one X chromosome, Xist spreads on the X, kicking off a plethora of events that ultimately results in stable X-linked gene repression, which is then faithfully transmitted to all daughter cells. The XCI process is tightly coupled to development and embryonic stem cell differentiation, and serves as an important model system to study epigenetic gene regulation. Previous studies performed in the laboratory aimed at unraveling the mechanism directing female specific initiation of XCI, revealed important new insights in the X chromosome counting and choice process (Monkhorst et al., Cell 2008). We also identified X-encoded RNF12 as a crucial XCI-activator (Jonkers et al., Cell 2009, Barakat et al., Plos Genet. 2010), regulating XCI through dose dependent breakdown of the embryonic stem cell specific protein REX1 (Gontan et al., Nature 2012). With the ERC consolidator grant we embarked on these findings and unraveled the feedback mechanism required to protect one X from being inactivated (Barakat et al., Mol Cell 2014), and studied the dynamics of XCI using new reporter alleles (Loos et al., MCB, 2015, Loos et al., MCB 2016). In addition, we have translated our findings to human model systems using an iPS cells (de Esch et al., Stem Cell Reports 2015, and Barakat et al., Stem Cell Reports 2015). These new insights form the basis for new exiting research related to XCI and epigenetic gene regulation in general.