Keywords: quantitative biology, gene regulation, epigenetics,
Requirements: Background in molecular and/or quantitative biology.
Dissecting quantitative information processing at the onset of X inactivation
collaboration with Annalisa Marsico
Biological networks can process quantitative information to elicit the appropriate cellular response. To identify the regulatory principles that govern quantitative information processing in mammalian cells, we study how information on X-chromosomal dosage and the differentiation state of the cell is integrated to initiate X-chromosome inactivation only in female cells and at the right developmental time. X inactivation is an essential developmental process, where one randomly chosen X chromosome is silenced in each female cell to ensure dosage compensation for X-linked genes between the sexes. The master regulator of X-inactivation is the long non-coding RNA Xist. We have developed a mathematical model of the Xist regulatory network that predicts the regulator types required to set up the correct Xist expression pattern (Mutzel et al., BioRxiv, 2017). Moreover, we have identified regulators of Xist that transmit information on X-dosage and differentiation through a series of pooled CRISPR screens.
In this project we will use quantitative biology approaches to identify the molecular mechanisms underlying the robust, X-dosage controlled molecular switch that governs Xist expression at the onset of X inactivation. To this end, the previously identified regulators will be perturbed experimentally in mouse embryonic stem cells. Perturbations will be performed both in a high-throughput manner using pooled CRISPR libraries and individually using targeted protein degradation, which allows a quantitative tuning of the regulator levels. In this way, non-linear thresholds and bistable behavior that are predicted by the Xist model will be identified and different hypotheses for the underlying mechanisms will be tested. Overall, the project aims at elucidating the mechanisms that allow accurate dosage sensing and that establish an epigenetic switch to stabilize the Xist expression pattern.
For more information visit the website of the Schulz lab.