Introduction

In humans, ~30% of the developing embryos terminate before implantation, and about 25% fail during the transition from gastrulation to organogenesis when cell fate and identity are set. The failure to specify cell fate and identity in a timely and robust manner results in developmental abnormalities and diseases. For example, 1 out of 100 children are born with congenital cardiac diseases, for the majority of which the causes are unknown. The Kurian lab investigates the regulatory principles that govern cell fate and identity during human cardiac development, homeostasis, and pathomechanisms of cardiac aging.

Figure 1

Fig. 1: Overarching research theme: The RNA regulatory principles of cardiac identity in embryogenesis, homeostasis, and aging in humans.

Our Research

The heart is the first organ to form and function during embryogenesis. The development of the heart is carefully choreographed by a series of precisely controlled cell fate decisions, which enables cardiac morphogenesis. A systematic understanding of molecular regulation of cardiac fate and identity is essential not only to understand the principles of self-organization of the human heart but also to develop therapeutic interventions for congenital and adult-onset cardiac disease. Our current understanding of the molecular regulation of cell fate and identity is mainly based on morphogen-mediated signal transduction, epigenetic, and transcriptional mechanisms. However, RNA is the primary language of communication from the genome, and it is distinctly regulated at each stage of its life cycle. We are only beginning to understand the RNA regulatory principles that govern cell fate decisions and cellular identity. Our lab is focused on understanding the RNA-centric processes (controlled by RNA binding proteins, non-coding RNAs, and regulatory motifs embedded in primary transcripts and mRNAs) and their regulatory logic that program cardiac cell fate and identity during human embryogenesis. In parallel, we study how the breakdown of RNA regulatory processes causes congenital and age-associated cardiac diseases. In close collaboration with the industry, we are developing personalized, non-immunogenic RNA therapeutics for congenital cardiac diseases.

Figure 2

Fig 2: Human cardiac organoids showing morphogenesis defect due to the loss of an embryonic translation specialization factor (Deniz Bartsch, Kurian lab)

Our Goals

Our long-term mission is to gain a systems-level understanding of the RNA regulatory principles that shape the self-organization and homeostasis of tissue and organs in humans in order to develop therapeutic solutions for tissue/ organ regeneration

The key questions we address are:

  • How is mRNA translation selectively controlled to program cell fate and identity?
  • How aging cuases loss of epegentic integrity and loss of transcriptional fidelity in the heart (CMMC Project)
  • What are the principles and mechanisms of divergent non-coding transcription emerging from developmental loci?
  • How is cardiac-specific pre-mRNA splicing regulated to build the contractility machinery?
  • How is transcriptional and translational fidelity maintained during homeostasis and breakdown with aging/ senescence?
  • How is mRNA translation dysregulated, causing pathological cardiac hypertrophy?
     

Our methods/techniques

We employ pluripotent stem cells and cell fate engineering (2D differentiation and organoid models)  in combination with systems biology and genome editing approaches to reconstruct and investigate human cardiac development and disease.

Figure 3

Fig. 3: Loss of a cardiac pre-mRNA splicing factor prevents sarcomerogenesis (white arrows) in human cardiomyocytes (Wenjie Yao (now: lead for single-cell genomics, Bayer Pharmaceuticals, Berkley) & Deniz Bartsch, Kurian lab)

Collaborators

Prof. Eric Van Nostrand, Baylor College of Medicine, USA
Prof. Michael Petrascheck, Scripps Research Institute, USA
Prof. Leos Shivaya Valasek, Czech Academy of Sciences, Czech Republic
Dr. Sasha Mendjan, Institute of Molecular Biotechnology, Vienna, Austria
Prof. Argyris Papantonis, University of Gottingen, DE
Prof. Malte Gather & Prof. Marcel Schubert, Humboldt Centre for Nano- and Biophotonics, University of Cologne
Prof. Christian Frezza, CECAD, Cologne
Prof. Dr. Aleksandra Trifunovic, CECAD, Cologne
Prof. Dr. Miguel A. Alejandre Alcázar, Faculty of Medicine, University of Cologne
Dr. Ina Huppertz, MPI-AGE, Cologne

Early detection and epigenetic rejuvenation strategies for age-associated cardiac dysfunctions in humans

Loss of transcriptional control has been proposed as a causal link to cardiac ageing. We discovered that DHS is a key molecular driver of age-associated cardiac episodes in humans by mediating the loss of transcriptional control.

A temporal decline in the functional and molecular integrity of an organism defines its ageing process. While multiple hallmarks of ageing have recently been enumerated, our understanding of their functional, molecular and temporal hierarchy remains incomplete.
The significance of these hallmarks in the ageing process vary in a tissue/ cell type specific manner. Considering the physiological differences between organs, it is conceivable that their susceptibility to these distinct triggers of ageing can differ. Therefore, it is important to delineate those mechanisms that influence the ageing process of specific organs to better understand organismal ageing. We investigate evolutionarily conserved mechanisms that leads to aging of the heart.

Figure 4

Fig. 4: DNA damage (green dots) in human hearts increases with age (Gaurav Ahuja (now: Associate Professor, IIIT Delhi), Kurian lab)

For further information regarding our research please visit

Laboratory for Developmental and Regenerative RNA Biology - Dr. Leo Kurian

  • Frank S, Ahuja G, Bartsch D, Russ N, Yao W,  Kuo JC, Derks JP,  Akhade VS, Kargapolova Y, Georgomanolis T, Messling J, Gramm M, Brant L, Rehimi R, Vargas N E†, Kuroczik†, Yang T P, Sahito R G A, Franzen J, Hescheler J, Sachinidis A, Peifer M, Rada-Iglesias A, Kanduri M, Costa I G, Kanduri C, Papantonis A, Kurian L. yylncT defines a class of divergently-transcribed lncRNAs and safeguards the T-mediated mesodermal commitment of human PSCs. Cell Stem Cell.2019 Feb 7;24(2):318-327.e8.
  • Bartsch D, Kalamkar K, Ahuja A, Bazzi H, Papantonis A, Kurian L Translational specialization in pluripotency by RBPMS poises future lineage-decisions. bioRxiv 2021.04.12.439420; https://doi.org/10.1101/2021.04.12.439420
  •  Josipovic N, Ebbesen KK, Zirkel A, Mackay-Danieli A, Dieterich C, Kurian L, Hansen TB, Papantonis A circRAB3IP modulates cell proliferation by reorganizing gene expression and mRNA processing in a paracrine manner.   bioRxiv, 27 Mar 2022 https://doi.org/10.1101/2022.03.25.485787
  • Ahuja G, Bartsch D, Yao W, Geissen S, Frank S, Aguirre A, Russ N, Messling J, Dodzian J, Lehmann K, Vargas N, Muck JS, Brodesser S, Baldus S, Sachinidis A, Hescheler J, Dieterich C, Trifunovic A, Papantonis A, Petrascheck M, Klinke A, Jain M, Valenzano D, Kurian L. Loss of genomic integrity by lysosphingolipid imbalance drives ageing in the heart. EMBO reports2019 Mar 18.
  • Chao-Chung Kuo, Sonja Hanzelmann, Nevcin Sentürk, Stefan Frank, Barna Zajzon, Jens-Peter Derks, Vijay Suresh Akhade, Gaurav Ahuja, Chandrasekhar Kanduri, Ingrid Grummt, Leo Kurian, and Ivan G. Costa.  Detection of RNA–DNA binding sites in long noncoding RNAs. Nucleic Acids Research.2019 Jan 30.  
  • Bender D, Kaczmarek AT, Santamaria-Araujoa JA, Stuevec B, Waltzc S, Bartsch D, Kurian L, Cirak S, Schwarz G. Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Human Molecular Genetics 2019 May 25.
  • Mondal T, Juvvuna PK, Kirkeby A, Mitra S, Kosalai ST, Traxler L, Hertwig F, Wernig-Zorc S, Miranda C, Deland L, Volland R, Bartenhagen C, Bartsch D, Bandaru S, Engesser A, Subhash S, Martinsson T, Carén H, Akyürek LM, Kurian L, Kanduri M, Huarte M, Kogner P, Fischer M, Kanduri C. Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis. Cancer Cell.2018 Mar 12;33(3):417-434.e7
  • Kurian L, Aguirre A, Sancho-Martinez I, Benner C, Hishida T, Nguyen TB, Reddy P, Nivet E, Nelles DA, Rodriguez Esteban C, Campistol JM, Yeo GW, Izpisua Belmonte JC Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation 2015;7;131(14):1278-90.
  • Galanjuk S, Zuhr E, Donmez A, Bartsch D, Kurian L, Tigges J, and Fritsche E (2022). The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing. Int J Mol Sci23. doi:10.3390/ijms23063295.
  • Kargapolova Y, Rehimi R, Kayserili H, Bruhl J, Sofiadis K, Zirkel A, Palikyras S, Mizi A, Li Y, Yigit G, Hoischen A, Frank S, Russ N, Trautwein J, van Bon B, Gilissen C, Laugsch M, Gusmao EG, Josipovic N, Altmuller J, Nurnberg P, Langst G, Kaiser FJ, Watrin E, Brunner H, Rada-Iglesias A, Kurian L, Wollnik B, Bouazoune K, and Papantonis A (2021). Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nat Commun12, 3014. doi:10.1038/s41467-021-23327-1.
  • Mitra S, Muralidharan SV, Marco MD, Juvvuna PK, Kosalai ST, Reischl S, Jachimowicz D, Subhash S, Raimondi I, Kurian L, Huarte M, Kogner P, Fischer M, Johnsen JI, Mondal T, and Kanduri C (2021). Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma. Cancer Res81, 1457-1471. doi:10.1158/0008-5472.CAN-19-3499.
  • Mitra S, Muralidharan SV, Di Marco M, Juvvuna PK, Kosalai ST, Reischl S, Jachimowicz D, Subhash S, Raimondi I, Kurian L, Huarte M, Kogner P, Fischer F, Johnsen JI,  Mondal T, Kanduri C: A p53 responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma through regulating p53 sub-cellular distribution. Cancer Research 2020 Dec 28:canres.3499.2019. doi: 10.1158/0008-5472.CAN-19-3499.
  • Laura Stanicek, Noelia Lozano-Vidal, Diewertje Ilse Bink, Aukie Hooglugt, Wenjie Yao, Ilka Wittig, Jos van Rijssel, Jaap Diederik van Buul, Anke van Bergen, Alina Klems, Anne Sophie Ramms, Ferdinand Le Noble, Patrick Hofmann, Robert Szulcek, Sheng Peng Wang, Stefan Offermanns, Meryem Seda Arslanoglu, Hyouk-Bum Kwon, Didier Stainier, Stephan Huveneers, Leo Kurian, Stefanie Dimmeler, Reinier Abraham Boon: Long non-coding RNA LASSIE regulates shear stress sensing and endothelial barrier function. Commun Biol. 2020 May 26;3(1):265. doi: 10.1038/s42003-020-0987-0.
  • Ahuja, G., Bartsch, D., Yao, W., Geissen, S., Frank, S., Aguirre, A., Russ, N., Messling, J.E., Dodzian, J., Lagerborg, K.A., Vargas, N.E., Muck, J.S., Brodesser, S., Baldus, S., Sachinidis, A., Hescheler, J., Dieterich, C., Trifunovic, A., Papantonis, A., Petrascheck, M., Klinke, A., Jain, M., Valenzano, D.R., and Kurian, L. (2019). Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart. EMBO Rep20.
  • Bender, D., Kaczmarek, A.T., Santamaria-Araujo, J.A., Stueve, B., Waltz, S., Bartsch, D., Kurian, L., Cirak, S., and Schwarz, G. (2019). Impaired mitochondrial maturation of sulfite oxidase in a patient with severe sulfite oxidase deficiency. Hum Mol Genet10.1093/hmg/ddz109.
  • Frank, S., Ahuja, G., Bartsch, D., Russ, N., Yao, W., Kuo, J.C., Derks, J.P., Akhade, V.S., Kargapolova, Y., Georgomanolis, T., Messling, J.E., Gramm, M., Brant, L., Rehimi, R., Vargas, N.E., Kuroczik, A., Yang, T.P., Sahito, R.G.A., Franzen, J., Hescheler, J., Sachinidis, A., Peifer, M., Rada-Iglesias, A., Kanduri, M., Costa, I.G., Kanduri, C., Papantonis, A., and Kurian, L. (2019). yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs. Cell Stem Cell24, 318-27 e8.
  • Keller T, Wengenroth L, Smorra D, Probst K, Kurian L, Kribs A, and Brachvogel B (2019). Novel DRAQ5/SYTOX(R) Blue Based Flow Cytometric Strategy to Identify and Characterize Stem Cells in Human Breast Milk. Cytometry B Clin Cytom 96, 480-9.
  • Kuo, C.C., Hanzelmann, S., Senturk Cetin, N., Frank, S., Zajzon, B., Derks, J.P., Akhade, V.S., Ahuja, G., Kanduri, C., Grummt, I., Kurian, L., and Costa, I.G. (2019). Detection of RNA-DNA binding sites in long noncoding RNAs. Nucleic Acids Res 47, e32.
  • Frank S, Ahuja G, Bartsch D, Russ N, Yao W, Kuo JC, Derks JP, Akhade VS, Kargapolova Y, Georgomanolis T, Messling JE, Gramm M, Brant L, Rehimi R, Vargas NE, Kuroczik A, Yang TP, Sahito RGA, Franzen J, Hescheler J, Sachinidis A, Peifer M, Rada-Iglesias A, Kanduri M, Costa IG, Kanduri C, Papantonis A, and Kurian L (2018). yylncT Defines a Class of Divergently Transcribed lncRNAs and Safeguards the T-mediated Mesodermal Commitment of Human PSCs. Cell Stem Cell10.1016/j.stem.2018.11.005.
  • Keller T, Wengenroth L, Smorra D, Probst K, Kurian L, Kribs A, and Brachvogel B (2018). Novel DRAQ5/SYTOX(R) Blue Based Flow Cytometric Strategy to Identify and Characterize Stem Cells in Human Breast Milk. Cytometry B Clin Cytom10.1002/cyto.b.21748.
  • Mondal T, Juvvuna PK, Kirkeby A, Mitra S, Kosalai ST, Traxler L, Hertwig F, Wernig-Zorc S, Miranda C, Deland L, Volland R, Bartenhagen C, Bartsch D, Bandaru S, Engesser A, Subhash S, Martinsson T, Caren H, Akyurek LM, Kurian L, Kanduri M, Huarte M, Kogner P, Fischer M, and Kanduri C (2018). Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis. Cancer Cell 33, 417-434 e417.
  • Palanimurugan R, Godderz D, Kurian L, and Jurgen Dohmen R (2018). Analysis of Cotranslational Polyamine Sensing During Decoding of ODC Antizyme mRNA. Methods Mol Biol 1694, 309-323.
  • Ju Lee H, Bartsch D, Xiao C, Guerrero S, Ahuja G, Schindler C, Moresco JJ, Yates JR, 3rd, Gebauer F, Bazzi H, Dieterich C, Kurian L, and Vilchez D (2017). A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells. Nat Commun 8, 1456.

 

Prof. Dr. Leo Kurian
Prof. Dr. Leo Kurian

Institute for Neurophysiology | CMMC Cologne

CMMC - PI - A 08

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Institute for Neurophysiology | CMMC Cologne

Robert-Koch-Str. 21

50931 Cologne

Publications - Leo Kurian

Link to PubMed

Affiliations
Group Members

Deniz Bartsch, PostDoc
Kalamkar Kaustubh, PhD student
Nachiket Pathek, PhD student
Mattias König, PhD student
Christoph Walter, Master student   
Andre Müller, Master student
Ayben Kakıcı, Bachelor student

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