Eckardt Treuter

Professor of Molecular Cell Biology Eckardt Treuter, Ph.D.

Work:
+46 8 524 810 60
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Address:
  • Center for Biosciences
    Department of Biosciences and Nutrition, Novum,
    Karolinska Institutet, SE-141 83 Stockholm, Sweden

Control of Metabolism and Inflammation by Transcriptional Coregulators

Our research attempts to uncover the multifaceted roles of transcriptional coregulators in human physiology and disease. The coregulators we study are ultimate components of nuclear receptor (NR) signaling pathways. They dictate cell type, target gene and ligand selectivity of transcription (1) by directly modulating NR function and (2) by mediating reversible epigenetic chromatin modifications linked to gene expression. Not surprisingly, alterations in function or expression of coregulators appear to be associated with human diseases and to cause individual genetic and epigenetic variations in physiology and disease.

We have early identified, by means of unbiased protein-protein interaction screenings, a large number of candidate coactivators and corepressors. Our work has in particular recognized and characterized founding members of a unique class of ligand-dependent (alias AF-2/LXXLL) corepressors. These include the metabolic corepressors RIP140 and PROX-1, but also the atypical orphan receptors SHP and DAX-1, which control distinct NR pathways governing cholesterol homeostasis. Additionally, we have developed expertise in elucidating structure and function of the ligand-binding domain, the molecular mechanisms of tamoxifen signaling, and the role of ubiquitin and SUMO modifications in transcriptional repression, all with an emphasis on coregulators.

Our most recent work investigates intriguing coregulator-dependent mechanisms that selectively trigger metabolic versus anti-inflammatory pathways governed by lipid-activated receptors such as LXRs (oxysterol receptors) and LRH-1 (a putative phospholipid receptor) in metabolic tissues and in the immune system. Of particular interest is the coregulator GPS2, a central component of sophisticated genomic positioning systems that facilitate genomic access of NRs in different contexts.

Encrypting the molecular, cellular and (patho-) physiological coregulator code is the ambitious long-term goal of our research. We hope in particular to gain a better understanding of the intricate links between metabolism and inflammation. Thereby, new possibilities to treat and prevent metabolic and inflammatory diseases (such as obesity, diabetes, atherosclerosis, non-alcoholic fatty liver disease, inflammatory bowel disease, and various cancers) should arise.

To achieve these goals we utilize a multidisciplinary approach involving

  • Genome-wide technologies - to reveal transcriptomes and epigenomes, thereby novel pathways and signaling components.
  • Conditional knockout/knock-in mice and RNA interference - to dissect pathways in vivo and to generate human disease models.
  • Synthetic NR ligands and compound screens - to reveal therapeutic potentials of signaling components.
  • Mechanistic studies - to develop models explaining the molecular interplay between ligands, NRs, coregulators, and epigenomes.
  • Clinical collaborations and method development  to identify genetic and epigenetic alterations that are associated with human diseases.

Selected publications

Toubal, A., Clément, K., Fan, R., Ancel, P., Pelloux, V., Rouault, C., Veyrie, N., Hartemann, A., Treuter, E. (shared corresponding author), and Venteclef, N.

SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation.

The Journal of Clinical Investigation Epub 2012 Dec 11.

Ehrlund, A., Jonsson, P., Vedin, L.L., Williams, C., Gustafsson, J.A., and Treuter, E.

Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFbeta, and Wnt/beta-catenin signaling in adrenocortical carcinoma cells.

PloS One 7, Epub 2012 Mar 9.

Venteclef, N., Jakobsson, T., Steffensen, K.R., and Treuter, E.

Metabolic nuclear receptor signaling and the inflammatory acute phase response

Trends in Endocrinology and Metabolism 22, 333-343.

Venteclef N., Jakobsson T., Ehrlund A., Damdimopoulos A.E., Mikkonen L., Ellis E., Nilsson L.M., Parini P., Jänne O.A., Gustafsson J.Å., Steffensen K.R., Treuter E.

GPS2-dependent corepressor / SUMO pathways govern anti-inflammatory actions of LRH-1 and LXR² in the hepatic acute phase response.

Genes & Development (2010) 24(4), 381-395.

Jakobsson T., Venteclef N., Toresson G., Damdimopoulos A.E., Ehrlund A., Lou X., Sanyal S., Steffensen K.R., Gustafsson J.Å., Treuter E.

GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus.

Molecular Cell (2009) 34(4):510-8.

Ehrlund A., Anthonisen-Holter E., Gustafsson N., Venteclef N., Robertson Remen K., Damdimopoulos A.E., Galeeva A., Pelto-Huikko M., Lalli E., Steffensen K.R., Gustafsson J.Å., Treuter E.

E3 ubiquitin ligase RNF31 cooperates with DAX-1 in transcriptional repression of steroidogenesis.

Molecular & Cellular Biology (2009) 29(8):2230-42.

Sanyal, S., Bavner,A., Haroniti A., Nilsson L.M., Lundåsen T., Rehnmark S., Witt M.R., Einarsson C., Talianidis I., Gustafsson J.Å., TREUTER E.

Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis.

Proc Natl Acad Sci U S A (2007) 104, 15665-70.

Press release 2010

Professor presentation 2007

Last modified by: Marie Franzén 2012-12-11