Professor Henriette Uhlenhaut

The Importance of Transcriptional Repression – Silencing Selected Genes

When Henriette Uhlenhaut talks about the need for silence, she does not mean the need to reduce noise, that is to relax and “switch off” from the hustle and bustle of everyday life. Rather, transcription repression switching off or silencing genes – is a main focus of her research activities. Uhlenhaut is interested in the mechanisms of gene regulation that underlie our body's hormonal responses. Through her research on transcriptional repression she is seeking to elucidate the mechanisms of how genes are inactivated. Her research findings could prevent the side effects of drugs like cortisone and thus help many sufferers of inflammatory diseases gain a new quality of life.

 

Prof. Dr. Henriette Uhlenhaut. Source: Helmholtz Zetrum München

Glucocorticoids like cortisone are the most common anti-inflammatory drugs. They belong to the class of steroid hormones and are used in numerous diseases such as allergies, asthma, rheumatoid arthritis, multiple sclerosis and some cancers. About three percent of the Western population takes steroids regularly. The sometimes drastic side effects include weight gain, bone loss, muscle wasting, and even diabetes. In the body's cells, glucocorticoids bind to receptors that play an important role in the regulation of metabolic processes.

Using next generation sequencing (NGS) technology, Uhlenhaut demonstrated for the first time that the glucocorticoid receptor binds directly to the DNA to switch off inflammatory genes. The dilemma here is that while the receptor – as intended inactivates inflammatory genes, it at the same time binds to other DNA sequences. It thereby activates metabolic genes that lead to the adverse side effects. With this finding, Uhlenhaut refuted the previous assumption that the receptor develops its anti-inflammatory effect through protein-protein interactions – a finding that is especially relevant for future therapeutic approaches and for which she received the Friedmund Neumann Prize in 2015. She is still seeking to elucidate why the transcription factor can simultaneously have both an activating and inactivating effect.

Unraveling the paradox

Together with her research group "Molecular Endocrinology" at the Institute for Diabetes and Obesity (IDO) of Helmholtz Zentrum München, she wants to further unravel this paradox. The hormone receptor affects not only inflammatory reactions, but also the glucose and lipid metabolism. For that reason, another new focus of the scientist and her team is the day-night rhythm: "Everyone gets up in the morning and goes to sleep in the evening. We are all controlled by this circadian rhythm, which affects every single cell in the body and also metabolism and hormones. Our research is particularly interested in how extensively the circadian rhythms are regulated by glucocorticoids and how much this internal clock must be taken into account, for example when prescribing drugs or planning therapies,“ Uhlenhaut said.

Molecular biology and genetics as key themes in her career

Her enthusiasm for molecular biology and genetics crystallized in the course of her studies at the Technical University of Braunschweig. This gave the impetus for Uhlenhaut to pursue this line of research more intensively during her diploma thesis at the Salk Institute in San Diego, where she studied the mechanisms of gene regulation in plants. Back in Germany, in her dissertation at the European Molecular Biology Laboratory (EMBL) in Heidelberg she focused more on disease-relevant topics. Using mouse models for human diseases, she explored the regulation of gene expression by transcription repression and recognized the importance of silencing specific genes: "While other research groups are working on the question of how to switch genes on, little research has been dedicated to the reverse mechanism – of switching genes off. That aroused my curiosity.“ Uhlenhaut succeeded in demonstrating in the animal model that a single gene, the forkhead transcription factor Foxl2, must be present in female mice throughout the entire lifetime to prevent transdifferentiation of ovaries into testes. Foxl2 together with the estrogen receptors inactivates male genes. This revolutionary finding was not only of central importance for the field of reproductive biology, but was a significant contribution towards the understanding of cellular plasticity in general.

Focus on hormone receptors

Uhlenhaut was encouraged by these findings, and during her research stays as postdoc at Salk Institute San Diego and at the Max Delbrück Center for Molecular Medicine Berlin (MDC), she increasingly focused on the question of how hormones once bound to their receptors – affect the genome, bind chromatin and regulate genes. Since 2013, Uhlenhaut heads the independent Emmy Noether Group "Molecular Endocrinology" at the Institute for Diabetes and Obesity (IDO). In 2014 she received a Starting Grant from the European Research Council (ERC). Enough tailwind to take a closer look at hormone receptors, especially the glucocorticoid receptors. “Each of us is under the influence of hormones every day. Without them we are not viable. I find it incredibly exciting how such complexity is encoded from only four bases (AGCT) and how our physiology works at the DNA level," Uhlenhaut said, describing her motivation.

Inspiring others to engage in the field

Starting in October 2018, she will be able to impart her enthusiasm for her subject to the students of Ludwig-Maximilians-Universität München (LMU). She will then give her inaugural lecture in her new position as Professor for "Metabolic Biochemistry and Genetics" at LMU in the Department of Biochemistry. "I am very much looking forward to this new position and to working with the students. And I am also glad to be a part of the LMU Gene Center and to work together in the Collaborative Research Centers 'Chromatin Dynamics' and 'Adrenal Hormones'," said Uhlenhaut about the new challenge.

In addition to her work as a professor, Henriette Uhlenhaut will continue her research at Helmholtz Zentrum München. Particularly in her research area, there are unresolved molecular puzzles: "It is still completely unclear how one and the same receptor within one and the same cell specifically switches some genes off and other genes on by binding to the same co-regulators and the same hormone," she said, describing the biological paradox that fascinates her so much. Through her research on transcription repression – switching off selected genes – she hopes to eliminate or at least alleviate the adverse side effects of glucocorticoid drugs.

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