Christoffels V.M.: Transcriptional mechanism controlling of heart pacemaker and conduction system formation

From 2001 I was taken on as a group leader to unravel the molecular basis of localized gene regulation and cell specification in the developing heart. In 2010 I was appointed professor of developmental biology in the department of Anatomy, Embryology & Physiology. My first breakthrough was the discovery that the location of development of the chambers and the atrioventricular canal in the heart tube is regulated by locally active T-box transcriptional repressors (Genes Dev. 2002). In 2005 I received an NWO VIDI grant to further study the role of T-box factors in the heart. A second breakthrough was the discovery that conduction system development is controlled by Tbx2 and Tbx3 (Genes Dev. 2007, Circ Res. 2008, PNAS 2012). Using genetic lineage analysis tools we addressed the contributions of different progenitor cells to the developing heart, and the role of T-box and other transcription factors in the formation of the pacemaker and conduction system components (Circ Res 2007-2010, Nature 2009). Our work on the development of the heart and conduction system has become internationally well recognized (Physiol Rev 2003, Circ Res. 2010). Recently, we uncovered a mechanism linking
developmental defects of the heart and ventricular pre-excitation (JCI 2011), and, using 4C-seq and transgenesis, identified a common genetic variant in the population that disrupts T-box factor binding and sodium channel gene enhancer function in vivo (JCI 2012, Nat Genet 2013, JCI 2014). Furthermore, using in vivo ChIP-seq, we uncovered a transcriptional and epigenetic mechanism for the specification of the atrioventricular canal of the heart involving GATA transcription factors and tissue-specific histone (de)acetylation (Nat Commun). Genetic variants in the human genome influence cardiac development and heart rhythm/arrhythmia risk. Current research focuses on identifying the transcriptional mechanisms underlying this phenomenon. Furthermore, we are exploring the transcriptional mechanisms that (re)program the pacemaker and conduction system cells of the heart. Theme: Cardiovascular Diseases This research group participates in Heart Failure Research Center