Systems Epigenetics Group

Dr. Edda Schulz

October 18, 2022

The Schulz lab studies epigenetic regulation with a systems biology approach. We seek to understand how threshold responses can establish transcriptional switches and epigenetic memory to allow quantitative information processing in mammalian cells. We use X-chromosome inactivation as a model to study epigenetic regulation, which is an essential developmental process. We complement our work on this biological question with synthetic biology approaches to uncover general rules that underlie quantitative gene control in mammalian cells. To solve fundamental problems in gene regulation we combining microscopy, genomics and genome engineering with mathematical modeling and computational biology.

For further information on the lab and the Institute visit the website of the Schulz lab.

We are looking for students with a passion to solve mysteries driving fundamental biological processes, and the willingness and ability to work in an interdisciplinary environment. Previous experience in mammalian stem cells, genome engineering, synthetic biology or computational biology is an advantage, but not a requirement.

Project 1: X-dosage-sensing for sex-specific gene expression

In mammals, females initiate the process of X-chromosome inactivation during early embryonic development. X inactivation is initiated through female-specific upregulation of the Xist RNA. This female-specificity is achieved through X-chromosomal dosage sensing. The project will aim at elucidating the principles employed by cells to reliably distinguish between a single and a double dose of X-linked genes. Specifically, the dose-response-relationships between several new Xist regulators, which our lab has recently identified through genetic screens, and Xist will be measured. Here the project will make use of a CRISPR-based tool we have recently developed to measure genetic dose-response curves within cells, called CasTuner (Noviello et al, BioRxiv, 2022). Through perturbation of candidate mechanisms, such as antisense transcription (see Mutzel et al, NSMB, 2019; Mutzel and Schulz, BioEssays, 2020), we will then elucidate, which principles shape the observed dose-response curve. In this way we hope to understand how cells can reliably sense X-dosage. Thereby the project will contribute to our overall understanding of how quantitative gene control is mediated in the mammalian genome.

Project 2: Intercellular heterogeneity at the Xist locus

At the onset of random X-chromosome inactivation, a symmetry-breaking event between the two X chromosomes in female cells must occur, such that one X will be inactivated and the other one will stay active. A key step in symmetry-breaking is heterogeneous upregulation of the Xist RNA. It remains unknown how this heterogeneity is generated and controlled at the molecular level. The project thus aims at (1) measuring heterogeneity of different events known to control Xist in cis and (2) assessing how perturbation of these events affect the Xist expression pattern. To this end, we will use single molecule footprinting (SMF) in collaboration with the Krebs lab (EMBL Heidelberg) to measure heterogeneity at different genomic regions at the Xist locus known to regulate Xist expression (see e.g., Gjaltema, Schwämmle et al, Mol Cell, 2022). Through perturbation of different mechanisms involved in Xist regulation, such as antisense transcription, H3K27me3 deposition at distal enhancers, Xist-controlling transcription factors and promoter methylation we will then dissect how the observed heterogeneity is precisely tuned. In this way we will advance our understanding of how gene expression is controlled across different regulatory layers.

Schulz