Skip to main content

Epigenomic control of metaflammation by nuclear receptor-coregulator pathways - Eckardt Treuter

We are interested in understanding the intricate relationship between metabolism and inflammation, referred to as ‘metaflammation’, which emerges as a key feature of the metabolic syndrome and its components obesity, insulin resistance, and type 2-diabetes.

Our research is driven by the hypothesis that closely linked metabolic and (anti-) inflammatory nuclear receptor-coregulator pathways play central roles in transcriptional and epigenomic mechanisms of disease. Specifically, we suspect that pathways involving the anti-inflammatory mediator GPS2 function as a critical molecular entry point for the integration of metabolic and inflammatory signals.

Anti-inflammatory GPS2 patways

So far, we have identified three key features of these pathways that appear highly disease-relevant: (1) Control of nuclear receptor cistromes (DNA binding) and epigenomes (histone modifications) at certain genes, such as the cholesterol transporter gene ABCG1. (2) Crucial component of anti-inflammatory transrepression by lipid-sensing nuclear receptors such as LXRs. (3) Dysregulation of an adipocyte-specific corepressor complex that controls inflammation in human obesity. Overall, these findings suggest that nuclear receptor-GPS2 pathways are directly involved in human metaflammatory diseases and potentially can be therapeutically modulated. Thus, our future work will further dissect these disease mechanisms, using mouse models and translational human studies, and also aim to develop novel anti-inflammatory treatment strategies.

Nuclear receptor-GPS2 pathways

Metaflammatory nuclear receptor-GPS2 pathways in physiology and disease: targets for therapeutic intervention. Molecular mechanisms: SUMOylated receptors (NRs) repress transcription of inflammatory genes (e.g. macrophage cytokine genes, liver acute phase genes) by docking to promoter-bound GPS2/corepressor (CoR) complexes linked to histone deacetylation, thereby preventing activation in response to inflammatory stimuli. SUMOylation is regulated by NR ligands and by intracellular signals in a dynamic, reversible, and cell-type dependent manner. Metabolites, endocrine disrupters, drugs and inflammatory signals may modulate the anti-inflammatory capacity of NRs. Physiological consequences and therapeutic possibilities: Highlighted are established and suspected tissues and diseases where NR/GPS2 pathways might occur. Envisaged are pharmacological approaches that selectively modulate NR-SUMOylation, GPS2/CoR interactions, or directly GPS2, all presenting new concepts for developing anti-inflammatory drugs to combat specific metaflammatory diseases.

Group members