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Molecular Medicine Partnership Unit

The MMPU is a joint venture between the Medical Faculty of the University of Heidelberg and the European Molecular Biology Laboratory (EMBL).

Heart Development and Disease

Group leaders: Eileen Furlong and Johannes Backs

Our research interest

Our team focuses on both fundamental and translational aspects of chromatin biology in the context of human heart development and disease including cardiomyopathies and acquired forms of acute/chronic heart failure. These heart diseases represent the most frequent underlying cause of death in western countries and thereby need an in depth investigation to develop new approaches to pave the way towards new translational approaches. Specific areas of interest include the mechanisms of epigenetic regulation down to the single cell level and the generation of tractable human in vitro 3D models (cardioids) that recapitulate the early steps of heart development and disease.

Background

Although a number of morphological heart defects can be addressed surgically, the genetic causes persist, and eventually result in heart failure and arrhythmias in adults. Mutations in transcription factors or chromatin modifiers lead to congenital heart disease, but very little is known about the pathomechanisms linking the specific genetic causes to cardiac dysfunction in adults. Mutations in chromatin modifying enzymes do not only cause neonatal and adult heart disease due to misregulation of gene expression, but also by stress-induced regulatory mechanisms that lead to secondarily heart disease.

Goals

This program aims to develop a human in vitro 3D model that recapitulates the early steps of heart development to form a 3D heart tube, which we will further exploit to make more complex heart organoids. Such a model will provide a genetically tractable system to study the molecular basis of both human heart development and genetic heart disease, especially when combined with gene perturbations and state-of-the-art single-cell technologies. We will use single-cell approaches (such as scATAC-seq) to follow the developmental trajectories of iPS cell differentiation with different protocols to develop a 3D system that best recapticulates human heart development. Having such 3D heart models in hand will enable a characterization of the functional impact of disease associated genetic variants. Chromatin remodeling will be assessed after genetic perturbations and also upon inflammatory stress, which we previously discovered leads to an acute de-compaction of chromatin. The combined expertise of both groups may lead to synergies to discover fundamental principles with translational potential to combat inherited and acquired heart disease.

Selected publications

The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.
Jebessa ZH, Shanmukha KD, Dewenter M, Lehmann LH, Xu C, Schreiter F, Siede D, Gong XM, Worst BC, Federico G, Sauer SW, Fischer T, Wechselberger L, Müller OJ, Sossalla S, Dieterich C, Most P, Gröne HJ, Moro C, Oberer M, Haemmerle G, Katus HA, Tyedmers J, Backs J. Nat Metab. 2019 Nov;1(11):1157-1167. doi: 10.1038/s42255-019-0138-4. Epub 2019 Nov 15. PMID: 31742248

Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression.
Ghavi-Helm Y, Jankowski A, Meiers S, Viales RR, Korbel JO, Furlong EEM. Nat Genet. 2019 Aug;51(8):1272-1282. doi: 10.1038/s41588-019-0462-3. Epub 2019 Jul 15. PMID: 31308546

O-GlcNAcylation of Histone Deacetylase 4 Protects the Diabetic Heart From Failure.
Kronlage M, Dewenter M, Grosso J, Fleming T, Oehl U, Lehmann LH, Falcão-Pires I, Leite-Moreira AF, Volk N, Gröne HJ, Müller OJ, Sickmann A, Katus HA, Backs J. Circulation. 2019 Aug 13;140(7):580-594. doi: 10.1161/CIRCULATIONAHA.117.031942. Epub 2019 Jun 14. PMID: 31195810

Inflammation leads through PGE/EP3 signaling to HDAC5/MEF2-dependent transcription in cardiac myocytes.
Tóth AD, Schell R, Lévay M, Vettel C, Theis P, Haslinger C, Alban F, Werhahn S, Frischbier L, Krebs-Haupenthal J, Thomas D, Gröne HJ, Avkiran M, Katus HA, Wieland T, Backs J. EMBO Mol Med. 2018 Jul;10(7):e8536. doi: 10.15252/emmm.201708536. PMID: 29907596

The cis-regulatory dynamics of embryonic development at single-cell resolution.
Cusanovich DA, Reddington JP, Garfield DA, Daza RM, Aghamirzaie D, Marco-Ferreres R, Pliner HA, Christiansen L, Qiu X, Steemers FJ, Trapnell C, Shendure J, Furlong EEM. Nature. 2018 Mar 22;555(7697):538-542. doi: 10.1038/nature25981. Epub 2018 Mar 14. PMID: 29539636

A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway.
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, Völkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schäfer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londoño JEC, Meder B, Freichel M, Gröne HJ, Most P, Müller OJ, Herzig S, Furlong EEM, Katus HA, Backs J. Nat Med. 2018 Jan;24(1):62-72. doi: 10.1038/nm.4452. Epub 2017 Dec 11. PMID: 29227474

Genetic variants regulating expression levels and isoform diversity during embryogenesis.
Cannavò E, Koelling N, Harnett D, Garfield D, Casale FP, Ciglar L, Gustafson HE, Viales RR, Marco-Ferreres R, Degner JF, Zhao B, Stegle O, Birney E, Furlong EE. Nature. 2017 Jan 19;541(7637):402-406. doi: 10.1038/nature20802. Epub 2016 Dec 26. PMID: 28024300

Group members

Victoria Mauz, MD
PhD student
Backs Group
Heidelberg University Hospital, Institute of Experimental Cardiology
Phone: +49 6221 56-7214
victoria.mauz@med.uni-heidelberg.de

On this page

  • Our research interest
  • Background
  • Goal
  • Selected publications
  • Group members

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