Transcriptional responses to signals and hormones

Gene expression changes in response to signaling cues like stress, infections, nutrition, circadian rhythms etc. are the basis of any cellular response. Every cell reacts in a specific way, depending on the tissue type or signaling pathways. Our aim is to understand transcriptional circuits and to describe the complexity of transcription factor interactions with co-regulators and the chromatin landscape using molecular biology, functional genomics, biochemistry and next-generation sequencing technologies.

1. Nuclear interaction partners of the glucocorticoid receptor

We performed chromatin-immunoprecipitation with subsequent mass spectrometry (ChIP-MS) to identify nuclear interaction partners of the glucocorticoid receptor in macrophages, liver and mouse embryonic fibroblasts (MEFs). Feel free to browse the results of those experiments here.
We are currently investigating the functions of some of those interaction partners in glucocorticoid-dependent inhibition of inflammation or regulation of metabolism.

a.) The role of the H3K4methyltransferase SETD1A for glucocorticoid-mediated gene regulation

SETD1A/COMPASS is recruited to Glucocorticoid Receptor occupied enhancers in macrophages and required for gene activation independent on changes in local H3K4methylation. Read more here.

b.) The role of the BRG1-containing chromatin remodelling complex in glucocorticoid sensitivity

That BRG1 is required for glucocorticoid-mediated gene activation was long known, however Aikaterini showed in her PhD project, that BRG1 is also required to prevent hyperinflammation suggesting a repressive role. Read the article here.

c.) C-terminal binding protein CTBP2 in macrophage inflammation

Activator or Repressor, the function of CtBPs in gene regulation is controversial. Benjamin not only showed that commonly used CtBP inhibitors appear to have off-target effects (see here) but also showed that CTBP2 acts as a transcriptional repressor in inflammation, but only in its oligomeric state.

2. Context-specific glucocorticoid receptor actions

Glucocorticoid actions are not only tissue-specific but also depend on the cellular context. Furthermore, we could recently show that the glucocorticoid response in macrophages depends on different co-regulators and the gene locus (see here, here or here). Here, we explore this locus-specific control of gene regulation by the glucocorticoid receptor using CRISPR/Cas9, next-generation sequencing and molecular biology techniques.

a.) Glucocorticoid-mediated gene repression

We have found that chromatin marks and DNA accessibility predict glucocortcoid-mediated gene activation, but not repression. On top, we found thet GR-bound enhancers associated with gene repression are enriched for NF-kB and STAT, but not the GR motif (see here). Here, we aim to elucidate the mechanisms of glucocorticoid-mediated gene repression for improved anti-inflammatory therapy.

3. Reversibility of long-term glucocorticoid effects

In this DFG funded project, we look at the long-term effects of glucocorticoid therapy in murine tissues. Glucocorticoids are widely prescribed to treat inflammatory diseases. The aim of this project is to understand glucocorticoid effects in non-immune cells to evaluate mechanisms involved in the adverse effects of glucocorticoid therapy. This project is a cooperation with Dr. Sabine Vettorazzi at the University of Ulm. We are using mouse models, histology, molecular biology, next-generation sequencing and single-cell analysis.