Ruprecht-Karls-Universität Heidelberg
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Lehmann0220 - Scientist (f/m) / PhD position
Project no:
Lehmann0220

Project leader:

Project supervisor:
Lehmann, Lorenz
Application deadline:
30. Nov 2020
Start of PhD project:
1. Jan 2021

Project description:

Title:
Epigenetic memory as a regulator of cardiac stress response
Summary:
Challenges for a personalized diagnostic and therapeutic approach to cardiac diseases are the individually different risk factors.
In addition to the genetic preconditions that every patient inevitably brings with him/her, he/she goes through a number of phases in his/her life that promote illness or health (e.g. phases of obesity, smoking or extensive sporting activity). This individual history may influence the heart's reaction to future stress situations (e.g. catecholamines). A molecular mechanism of this observation has not yet been reliably proven in the heart.
Epigenetic alterations can lead to modifications of pathological or protective genes, so that they behave differently in stress situations. A certain class of genomic regions, the enhancers, are of particular interest here. They not only regulate the transcription of one gene, but can also interact with multiple genes due to the 3-dimensional folding of DNA. Transcriptional activation is always preceded by enhancer activation, and can therefore be permanently altered without direct expression changes (or measurable clinical phenotype). In preliminary experiments, we have identified a genomic regions with characteristics of a superenhancer that is activated on stress and stays activated even when stress-conditions are normalized again. This region is a perfect candidate for epigenetic memory. We generated three different conditional knockout mice (two enhancer and one coding region in this locus) to study the biological impact of this genomic region. In collaboration we additionally aim to epigenetically activate this region in vivo by using a modified dCas9-approach.
References:
1. Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, Dewenter M, Sramek V, Oehl U, Krebs-Haupenthal J, von der Lieth AH, Schmidt A, Sun Q, Ritterhoff J, Finke D, Volkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schafer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londono JEC, Meder B, Freichel M, Grone HJ, Most P, Muller OJ, Herzig S, Furlong EEM, Katus HA and Backs J. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med. 2018;24:62-72.

2. Lehmann, L. H., Worst, B. C., Stanmore, D. A., and Backs, J. (2014) Histone deacetylase signaling in cardioprotection. Cell Mol Life Sci 71, 1673-1690

3. Backs, J., Worst, B. C., Lehmann, L. H., Patrick, D. M., Jebessa, Z., Kreusser, M. M., Sun, Q., Chen, L., Heft, C., Katus, H. A., and Olson, E. N. (2011) Selective repression of MEF2D activity by PKA-dependent proteolysis of HDAC4. J Cell Biol 195, 403-415

4. Hohl, M., Wagner, M., Reil, J. C., Muller, S. A., Tauchnitz, M., Zimmer, A. M., Lehmann, L. H., Thiel, G., Bohm, M., Backs, J., and Maack, C. (2013) HDAC4 controls histone methylation in response to elevated cardiac load. J Clin Invest 123, 1359-1370

5. Lehmann, L. H., Rostosky, J. S., Buss, S. J., Kreusser, M. M., Krebs, J., Mier, W., Enseleit, F., Spiger, K., Hardt, S. E., Wieland, T., Haass, M., Luscher, T. F., Schneider, M. D., Parlato, R., Grone, H. J., Haberkorn, U., Yanagisawa, M., Katus, H. A., and Backs, J. (2014) Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling. Proc Natl Acad Sci U S A 111, 13499-13504
Methods that will be used:
Western Blot, Cell culture of primary neonatal and adult cardiomyocytes, animal work with conditional knockout animals, ChIPseq, ChIP-PCR, HiC, siRNA approaches, Luziferase assays.
Cooperation partners:
Laura Zelarayan, MD, Institut für Pharmakologie und Toxikologie, Universitätsmedizin Göttingen
Personal qualifications:
We look for a person with a master or equivalent degree in biology or any related field with a strong background in molecular biology and advanced tissue culture experience. Ideally the person has already worked with animals (FELASA A is helpful but not crucial).
You fit to us if you want to work in a world-class research environment with state-of-the-art equipment and access to comprehensive research facilities. You have the ability to work independently, but also show a strong team spirit.
Keywords:
Epigenetics; epigenetic memory, metabolic stress, heart, ChIP