Die Verknüpfung von Glukokortikoidrezeptorbindung und Genregulation im endogenen genomischen Kontext
Zusammenfassung der Projektergebnisse
Embryonic stem cells (ESCs) can differentiate into any cell type, making them valuable models for studying gene regulation. Using STARR-seq, we created a genome-wide enhancer activity map of murine ESCs (mESCs) in both pluripotent and early differentiation states and identified active enhancers, their sequence motifs, and associated chromatin features. CRISPR/Cas9 deletions confirmed that specific enhancers we identified indeed regulate nearby genes Together, our genome-wide enhancer activity map elucidates features associated with enhancer activity levels, identifies regulatory regions disregarded by computational prediction tools, and provides a resource for future studies into regulatory elements in mESCs. Accordingly, the data we generated was also used to develop a new enhancer prediction tool called CRUP. In a separate study funded by this grant, we studied how exposure to stress is linked to an increased risk of various psychiatric disorders, with its long-term effects potentially influenced by genetic variants. Using a high-throughput enhancer assay, we identified genetic variants within regulatory elements that impact the transcriptomic response to glucocorticoids, a key stress hormone. These variants are enriched in those associated with psychiatric disorders and neurobehavioral traits and affect transcripts altered in the postmortem brains of individuals with psychiatric conditions. Additionally, they correlate with changes in the physiological stress response. Collectively, this suggests that these functional variants may play a causal role in psychopathology by modulating stress-responsive gene expression and physiological stress regulation.
Projektbezogene Publikationen (Auswahl)
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CRUP: a comprehensive framework to predict condition-specific regulatory units. Genome Biology, 20(1).
Ramisch, Anna; Heinrich, Verena; Glaser, Laura V.; Fuchs, Alisa; Yang, Xinyi; Benner, Philipp; Schöpflin, Robert; Li, Na; Kinkley, Sarah; Römer-Hillmann, Anja; Longinotto, John; Heyne, Steffen; Czepukojc, Beate; Kessler, Sonja M.; Kiemer, Alexandra K.; Cadenas, Cristina; Arrigoni, Laura; Gasparoni, Nina; Manke, Thomas ... & Vingron, Martin
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Assessing genome-wide dynamic changes in enhancer activity during early mESC differentiation by FAIRE-STARR-seq. Nucleic Acids Research, 49(21), 12178-12195.
Glaser, Laura V.; Steiger, Mara; Fuchs, Alisa; van Bömmel, Alena; Einfeldt, Edda; Chung, Ho-Ryun; Vingron, Martin & Meijsing, Sebastiaan H.
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High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders. Proceedings of the National Academy of Sciences, 120(49).
Penner-Goeke, Signe; Bothe, Melissa; Rek, Nils; Kreitmaier, Peter; Pöhlchen, Dorothee; Kühnel, Anne; Glaser, Laura V.; Kaya, Ezgi; Krontira, Anthi C.; Röh, Simone; Czamara, Darina; Ködel, Maik; Monteserin-Garcia, Jose; Diener, Laura; Wölfel, Barbara; Sauer, Susann; Rummel, Christine; Riesenberg, Stephan; Arloth-Knauer, Janine ... & Binder, Elisabeth B.
