Christoffels group – Development of heart and rhythm

Each day, children are born with a life-threatening heart defect, and many individuals suffer from heart a disease such as a rhythm disorder. Because the risk of these diseases is defined by genetic alterations, our research group studies the molecular genetic processes of heart development and rhythm establishment. Our goal is to understand how congenital heart defects and arrhythmias develop, and how this is influenced by individual variations in genome function. We use transgenic mice to model genetic heart defects and to study the function of the genome in heart development and function. The lab projects use a wide range of approaches and technologies, such as in vivo genome editing (CRISPR-Cas9), transcriptomics, epigenomics (RNA-seq, ATAC-seq, ChIP-seq, 4C-seq, etc.), bioinformatics, embryo culture, tissue culture, cell and molecular biology, microscopy, morphometrics, 3D reconstruction, and electrophysiological assays.

Contact: V.M. Christoffels (

Research overview

Under construction – coming soon

2. Improving hyperthermia-based clinical cancer treatments.

Hyperthermia and cancer. Hyperthermia (HT) – temporary elevation of tumor temperature to 41-43 °C – alters many aspects of cellular metabolism, but its effects on DNA repair are of special interest in the context of cancer research and treatment. HT inhibits repair of DNA double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer with proven clinical track record in combination therapy for various types of cancer, including breast, bladder, head, neck, melanoma, soft tissue sarcoma and cervix.

Problem. The efficacy of HT treatments is negatively affected by a number of factors, such as insufficient thermal dose, temporary nature of HT effects (resulting in a short therapeutic window) and thermotolerance (induction of a temporary resistance to subsequent HT treatments). It is thus evident that outcomes of HT therapies would benefit from strategies to: (I) Increase HT efficacy at lower temperatures and shorter treatments; (II) extend the duration of the therapeutic window and (III) eliminate or reduce thermotolerance.

Results. Recently, we found that a short incubation of cervix cancer cells in the presence of a HSP90 inhibitor ganetespib enhances the effects of concomitant HT treatment in vitro, nearly without affecting non-heated cells. In particular, ganetespib (i) potentiated cytotoxic as well as radiosensitizing and chemosensitizing effects of HT; (ii) enhanced HT-mediated induction of DNA damage; (ii) reduced thermotolerance and (iii) prolonged and enhanced the effects of HT on DSB repair. Our preliminary results thus establish HSP90 inhibition as a straightforward and efficient approach to improve HT treatment efficacy with no or limited systemic toxicity.

Aims. We are currently investigating the effects of HSP90 inhibition on the efficacy of anticancer treatments involving HT in animal models of cancer, in vivo. The long-term goal of our study is boosting the effectiveness of HT treatments in the clinic.

Relevance. We are confident that positive results of our current in vivo studies will find their way into clinical practice. Together with clinicians of AMC and EMC, we are already considering various groups of patients that would most benefit from our improved treatments. Since ganetespib has a favorable safety profile and is already used clinically, we are convinced that the first trials could be initiated in the near future.

Figure 4. Schematic representation of combination therapies involving DNA-damaging agents, HT and HSP90


Alex Postma, senior scientist (
Antoinette van Ouwerkerk, PhD student (
Bjarke Jensen, senior scientist (
Corrie de Gier-de Vries, technician (
Fernanda Bosada, postdoc (
Henk van Weerd, PhD student (
Jaeike Faber, PhD student (group Jensen) (
Jianan Wang, PhD student (group Boink) (
Joyce Man, PhD student (
Karel van Duijvenboden, scientist (
Marie Günthel, PhD student (
Phil Barnett, senior scientist (
Vincent Christoffels, PI, group leader (
Vincent van Eif, PhD student (
Vincent Wakker, technician (

  1. Man J, Barnett P, Christoffels VM. Structure and function of the Nppa-Nppb cluster locus during heart development and disease. Cell Mol Life Sci. 2018 Apr;75(8):1435-1444.
  2. Woudstra OI, Ahuja S, Bokma JP, Bouma BJ, Mulder BJM, Christoffels VM. Origins and consequences of congenital heart defects affecting the right ventricle. Cardiovasc Res. 2017 Oct 1;113(12):1509-1520.
  3. Jensen B, Vesterskov S, Boukens BJ, Nielsen JM, Moorman AFM, Christoffels VM, Wang T. Morpho-functional characterization of the systemic venous pole of the reptile heart. Sci Rep. 2017 Jul 27;7(1):6644.
  4. de Bakker BS, de Jong KH, Hagoort J, de Bree K, Besselink CT, de Kanter FE, Veldhuis T, Bais B, Schildmeijer R, Ruijter JM, Oostra RJ, Christoffels VM, Moorman AF. An interactive three-dimensional digital atlas and quantitative database of human development. Science. 2016 Nov 25;354(6315). pii: aag0053.
  5. Jensen B, van der Wal AC, Moorman AFM, Christoffels VM. Excessive trabeculations in noncompaction do not have the embryonic identity. Int J Cardiol. 2017 Jan 15;227:325-330.
  6. Lüdtke TH, Rudat C, Wojahn I, Weiss AC, Kleppa MJ, Kurz J, Farin HF, Moon A, Christoffels VM, Kispert A. Tbx2 and Tbx3 Act Downstream of Shh to Maintain Canonical Wnt Signaling during Branching Morphogenesis of the Murine Lung. Dev Cell. 2016 Oct 24;39(2):239-253.
  7. van Duijvenboden K, de Boer BA, Capon N, Ruijter JM, Christoffels VM. EMERGE: a flexible modelling framework to predict genomic regulatory elements from genomic signatures. Nucleic Acids Res. 2016 Mar 18;44(5):e42. doi:10.1093/nar/gkv1144
  8. Nadadur RD, Broman MT, Boukens B, Mazurek SR, Yang X, van den Boogaard M, Bekeny J, Gadek M, Ward T, Zhang M, Qiao Y, Martin JF, Seidman CE, Seidman J, Christoffels V, Efimov IR, McNally EM, Weber CR, Moskowitz IP. Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Sci Transl Med. 2016 Aug 31;8(354):354ra115.
  9. Burger NB, Haak MC, Kok E, de Groot CJ, Shou W, Scambler PJ, Lee Y, Cho E, Christoffels VM, Bekker MN. Cardiac defects, nuchal edema and abnormal lymphatic development are not associated with morphological changes in the ductus venosus. Early Hum Dev. 2016 Oct;101:39-48.
  10. Sergeeva IA, Hooijkaas IB, Ruijter JM, van der Made I, de Groot NE, van de Werken HJ, Creemers EE, Christoffels VM. Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress. Development. 2016 Jun 15;143(12):2135-46.
  11. van Weerd JH, Christoffels VM. The formation and function of the cardiac conduction system. Development. 2016 Jan 15;143(2):197-210.
  12. Boukens BJ, Coronel R, Christoffels VM. Embryonic development of the right ventricular outflow tract and arrhythmias. Heart Rhythm. 2016 Feb;13(2):616-22.
  13. Postma AV, Bezzina CR, Christoffels VM. Genetics of congenital heart disease: the contribution of the noncoding regulatory genome. J Hum Genet. 2016 Jan;61(1):13-9.
  14. Stefanovic S, Christoffels VM. GATA-dependent transcriptional and epigenetic control of cardiac lineage specification and differentiation. Cell Mol Life Sci. 2015 Oct;72(20):3871-81.
  15. Gillers BS, Chiplunkar A, Aly H, Valenta T, Basler K, Christoffels VM, Efimov IR, Boukens BJ, Rentschler S. Canonical wnt signaling regulates atrioventricular junction programming and electrophysiological properties. Circ Res. 2015 Jan 30;116(3):398-406.
  16. Osterwalder M, Speziale D, Shoukry M, Mohan R, Ivanek R, Kohler M, Beisel C, Wen X, Scales SJ, Christoffels VM, Visel A, Lopez-Rios J, Zeller R. HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme. Dev Cell. 2014 Nov 10;31(3):345-57.
  17. Mohan RA, van Engelen K, Stefanovic S, Barnett P, Ilgun A, Baars MJ, Bouma BJ, Mulder BJ, Christoffels VM, Postma AV. A mutation in the Kozak sequence of GATA4 hampers translation in a family with atrial septal defects. Am J Med Genet A. 2014 Nov;164A(11):2732-8.
  18. van Weerd JH, Badi I, van den Boogaard M, Stefanovic S, van de Werken HJ, Gomez-Velazquez M, Badia-Careaga C, Manzanares M, de Laat W, Barnett P, Christoffels VM. A large permissive regulatory domain exclusively controls Tbx3 expression in the cardiac conduction system. Circ Res. 2014 Aug 1;115(4):432-41.
  19. van Duijvenboden K, Ruijter JM, Christoffels VM. Gene regulatory elements of the cardiac conduction system. Brief Funct Genomics. 2014 Jan;13(1):28-38.
  20. Christoffels VM, Pu WT. Developing insights into cardiac regeneration. Development. 2013 Oct;140(19):3933-7.
  21. Sergeeva IA, Hooijkaas IB, Van Der Made I, Jong WM, Creemers EE, Christoffels VM. A transgenic mouse model for the simultaneous monitoring of ANF and BNP gene activity during heart development and disease. Cardiovasc Res. 2014 Jan 1;101(1):78-86.
  22. van den Boogaard M, Smemo S, Burnicka-Turek O, Arnolds DE, van de Werken HJ, Klous P, McKean D, Muehlschlegel JD, Moosmann J, Toka O, Yang XH, Koopmann TT, Adriaens ME, Bezzina CR, de Laat W, Seidman C, Seidman JG, Christoffels VM, Nobrega MA, Barnett P, Moskowitz IP. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest. 2014 Apr;124(4):1844-52.
  23. Stefanovic S, Barnett P, van Duijvenboden K, Weber D, Gessler M, Christoffels VM. GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development. Nat Commun. 2014 Apr 28;5:3680.
  24. van den Boogaard M, Wong LY, Tessadori F, Bakker ML, Dreizehnter LK, Wakker V, Bezzina CR, ‘t Hoen PA, Bakkers J, Barnett P, Christoffels VM. Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. J Clin Invest. 2012 Jul;122(7):2519-30.
  25. Barnett P, van den Boogaard M, Christoffels V. Localized and temporal gene regulation in heart development. Curr Top Dev Biol. 2012;100:171-201. doi:10.1016/B978-0-12-387786-4.00004-X
  26. Bakker ML, Boink GJ, Boukens BJ, Verkerk AO, van den Boogaard M, den Haan AD, Hoogaars WM, Buermans HP, de Bakker JM, Seppen J, Tan HL, Moorman AF, ‘t Hoen PA, Christoffels VM. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res. 2012 Jun 1;94(3):439-49.
  27. Frank DU, Carter KL, Thomas KR, Burr RM, Bakker ML, Coetzee WA, Tristani-Firouzi M, Bamshad MJ, Christoffels VM, Moon AM. Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis. Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):E154-63.
  28. Singh R, Hoogaars WM, Barnett P, Grieskamp T, Rana MS, Buermans H, Farin HF, Petry M, Heallen T, Martin JF, Moorman AF, ‘t Hoen PA, Kispert A, Christoffels VM. Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation. Cell Mol Life Sci. 2012 Apr;69(8):1377-89.
  29. Mesbah K, Rana MS, Francou A, van Duijvenboden K, Papaioannou VE, Moorman AF, Kelly RG, Christoffels VM. Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis. Hum Mol Genet. 2012 Mar 15;21(6):1217-29.
  30. Christoffels V. Regenerative medicine: Muscle for a damaged heart. Nature. 2011 Jun 29;474(7353):585-6.
  31. Aanhaanen WT, Boukens BJ, Sizarov A, Wakker V, de Gier-de Vries C, van Ginneken AC, Moorman AF, Coronel R, Christoffels VM. Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice. J Clin Invest. 2011 Feb;121(2):534-44.
  32. Sizarov A, Ya J, de Boer BA, Lamers WH, Christoffels VM, Moorman AF. Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation. 2011 Mar 15;123(10):1125-35.
  33. Aanhaanen WT, Mommersteeg MT, Norden J, Wakker V, de Gier-de Vries C, Anderson RH, Kispert A, Moorman AF, Christoffels VM. Developmental origin, growth, and three-dimensional architecture of the atrioventricular conduction axis of the mouse heart. Circ Res. 2010 Sep 17;107(6):728-36.
  34. Singh R, Horsthuis T, Farin HF, Grieskamp T, Norden J, Petry M, Wakker V, Moorman AF, Christoffels VM, Kispert A. Tbx20 interacts with smads to confine tbx2 expression to the atrioventricular canal. Circ Res. 2009 Aug 28;105(5):442-52.
  35. Horsthuis T, Buermans HP, Brons JF, Verkerk AO, Bakker ML, Wakker V, Clout DE, Moorman AF, ‘t Hoen PA, Christoffels VM. Gene expression profiling of the forming atrioventricular node using a novel tbx3-based node-specific transgenic reporter. Circ Res. 2009 Jul 2;105(1):61-9.
  36. Aanhaanen WT, Brons JF, Domínguez JN, Rana MS, Norden J, Airik R, Wakker V, de Gier-de Vries C, Brown NA, Kispert A, Moorman AF, Christoffels VM. The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle. Circ Res. 2009 Jun 5;104(11):1267-74.
  37. Christoffels VM, Grieskamp T, Norden J, Mommersteeg MT, Rudat C, Kispert A. Tbx18 and the fate of epicardial progenitors. Nature. 2009 Apr 16;458(7240):E8-9; discussion E9-10.