Joost Gribnau Group
X chromosome inactivation
My research group is interested in research questions related to mechanisms involved in regulation of gene dosage, and the consequences of gene dosage imbalances on cell homeostasis and disease. One of our main lines of research focusses on different aspects of the X-chromosome inactivation (XCI) process. This process is mammalian specific and leads to one transcriptionally inactive X chromosome in every female cell, to compensate for dosage differences of X encoded genes between male and female cells. Our studies aimed to unravel 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).
Our recent work indicates that loss of Rnf12 leads to loss of XCI, which is surprisingly well tolerated in a chimaeric context (Barakat Mol. Cell 2014), and provided new insights in the silencing mechanism (Loda et al., Nature Com. 2017). These findings opened several new lines of research, and provided a powerful model system to investigate the role of X chromosome reactivation in cancer. Our interest in stem cells as a model system to study XCI has sparked many other lines of research, and formed the basis for the establishment of the Erasmus MC iPS facility, which generates and genetically manipulates patient specific iPS cells for the scientific community.
Recently, we developed novel technology enabling retrospective gene expression analysis through stable epigenetic marking of active genes. In addition, we have developed new technology to determine genome wide DNA methylation profiles at very low cost (Boers et al., Genome Res. 2018), and are currently refining this technology to generate single cell DNA methylation profiles. These novel technologies will be applied to identify tissue specific stem cells, to study cancer progression and to address questions related to the role of cancer stem cells in tumorigenesis.