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Pathophysiological role of nuclear receptor signalling

Pathophysiological role of nuclear receptor signalling

DEPARTMENT

Functional genomics and cancer

TEAM LEADER

Daniel METZGER

Steroid (e.g. androgens, estrogens, corticoids) and secosteroid (e.g. vitamin D) hormones play a key role in the development and cellular homeostasis of mammals. The activity of these hormones is mediated by proteins belonging to the nuclear receptor superfamily. The hormone-receptor pair functions as a highly selective lock-and-key system that modulates the expression of many genes and the activities of target cells.
Androgens and estrogens are essential for sexual maturation, corticoids are involved in the control of circadian activities and stress effects, and vitamin D regulates blood calcium levels. Moreover, due to their effects on metabolism, proliferation and inflammation, their receptors are therapeutic targets for pathologies refractory to current treatments such as various autoimmune and rare diseases, as well as cancers.
The objective of the laboratory is to understand the effects of these hormones under physiological and pathophysiological conditions in the whole organism. Our studies allow the characterization of the molecular and cellular events underlying the activity of these hormones, as well as the identification of new therapeutic targets for numerous pathologies with poor effective treatments.

 

Open post-doctoral position : www.igbmc.fr/igbmc/emplois/igbmc-post-doc-dmetzger-post-doctoral-position-at-the-institute-of-genetics-and-molecular-and-cellular-biology

Research subgroup(s)

Members

Researchers

Post-doctoral fellows

PhD students

Technicians

Occasionnal collaborators

Current projects

General strategy
Nuclear receptors are transcription factors that transduce hormone signaling into a transcriptional response. The activity of about two-thirds of the 48 nuclear receptors is controlled by selective ligands (e.g. steroid hormones, retinoids, intracellular lipids), and is fine-tuned by transcriptional coregulators forming macromolecular complexes that activate (coactivators) or repress (corepressors) the expression of target genes by modulating the accessibility of the transcriptional machinery to DNA.


The various projects of the laboratory aim at understanding the effects of steroid hormones and vitamin D under physiological and pathophysiological conditions in the whole organism, using conditional somatic mutagenesis techniques (CreERT2) developed in the laboratory. Using an integrative biology approach combining phenotypic and genomic analyses, we characterize transcriptomic (e.g. RNA-seq) and proteomic (e.g. mass spectrometry) modifications, as well as the chromatin organization (e.g. ChIP-seq, ATAC-seq), in mouse models mimicking human pathologies. In parallel, we are developing single-cell analysis tools (e.g. flow cytometry, single-cell RNA-seq, ATAC-seq, spatial transcriptomics) to identify and characterize the cell populations involved in pathogenesis.


Benefits and impact
The various collaborations and our network of experts facilitate the validation of our results on human samples, and will improve our knowledge of the mechanisms underlying cellular homeostasis, as well as allow the development of new therapeutic options. In addition, a better understanding of the tissue-specific actions of these receptors will facilitate the design of new therapeutic agents with selective activities and thus fewer side effects.

Resources

Recent publication : https://doi.org/10.15252/emmm.202217209.

Julie Terzic, Mohamed A. Abu el Maaty, Régis Lutzing, Alexandre Vincent, Rana El Bizri, Matthieu Jung, Céline Keime and Daniel Metzger (2023). Hypoxia-inducible factor 1A inhibition overcomes castration resistance of prostate tumors. EMBO Molecular Medicine. e17209

Collaborations and networks

Collaborations

  • Pr. Arnaud Ferry, Institute of Myology, Paris, France
  • Prof. Bernard Geny, Institute of Physiology, Faculty of Medicine, Strasbourg, France
  • Pr. Vincent Goffin, Institut Necker Enfants Malades, Paris, France
  • Dr. Sandrine Henry, Immunology Center of Marseille, France
  • Dr. Bruno Klaholz and Dr. Isabelle Billas, IGBMC, France
  • Pr. Hervé Lang, Urology Department, University Hospitals of Strasbourg, France
  • Dr. Véronique Lindner, Department of Pathology, University Hospitals of Strasbourg, France
  • Prof. Agnès Linglart, Pediatric Endocrinology-Diabetology Service, Assistance publique - Hôpitaux de Paris, France
  • Pr. Alain Meyer, Institute of Physiology, Faculty of Medicine, Strasbourg, France
  • Dr. Arnaud Molin, Department of Genetics, University Hospital of Caen, France
  • Pr. Natalia Prevarskaya, Laboratory of Cellular Physiology, Lille, France
  • Dr. Natacha Rochel, IGBMC, France
  • - Prof. Jan Tuckermann, University of Ulm, Germany

Networks

  • Filière OSCAR, a national netwrk for rare bone, calcium and cartilage diseases
  • Cancéropôle Est

Funding and partners

  • French Association against Myopathies (AFM)
  • Foundation for Medical Research (FRM)
  • National Cancer Institute (INCa)
  • League Against Cancer
  • National Research Agency (ANR)
  • Rare Diseases Foundation
  • ARC Foundation

News

Androgen receptor coordinates metabolic and contractile functions of skeletal muscle

Androgens are steroid hormones that affect muscle structure and strength whose action is mediated by the androgen receptor. In a study published in…

Read more

Awards and recognitions

Daniel Metzger

  • Grand Prix René Turpin de Cancérologie / Fondation de l’Institut de France (2016)
  • Membre élu de l’EMBO (2013)
  • Membre élu de l’European Academy of Cancer Sciences (2012)
  • Médaille d’argent du CNRS (2010)
  • Grand Prix Jules Martin de l'Académie des Sciences (2007)
  • Prix Janine Courrier de l'Académie des Sciences (1999)

Post-doctorants

  • Daniela Rovito – Prix jeune chercheur OSCAR (2021)

Doctorants

  • Delphine DUTEIL - Prix de thèse - Conseil scientifique de l'Université de Strasbourg (2011)
  • Vanessa UEBERSCHLAG - Palmarès prix de thèse SBS : Prix de la Région du Grand Est - Société de Biologie de Strasbourg (2017)
  • Darya YANUSHKO - best Oral Presentation award at the Canceropole-Est Forum (2023)
  • Darya YANUSHKO - Poster prize at the 32nd journée scientifique de l'ARTP (2023)

Publications

Functional genomics and cancer - Cancer research - Rare diseases - Regenerative medicine