Shoumo Bhattacharya MA, MD, MSc, FRCP, FMedSci
- Reproduction, Development and Genetics
- Cardiovascular Science
- Sheny Chen
- Dorota Szumska
- Catherine Cosgrave
- Matt Benson
- Carol Broadbent
- Milena Ciorach
- Daniel Andrew
- Anuja Neve
- Julie de Mesmaeker
- Dr Jurgen Scheider
- Prof Stefan Neubauer
- Prof Kieran Clarke
- Dr Tim Mohun, NIMR
- Dr Mark Henkelman, Toronto
- Dr John Sled, Toronto
- Prof Steve Brown, Harwell
- Maarten van Lohuizen, NKI, Amsterdam
- Harukiko Koseki, RIKEN
- Dr Antonio Baldini, TIGEM, Naples
- Prof Peter Scrambler, ICH, London
- Dr Robert Kelly, Marseilles
- Dr Vincent Christoffels, Amsterdam
- Dr Silke Sperling, Berlin
- Annik Prat, IRCM, Montreal
- Nabil Seidah, IRCM. Montreal
- GO-CHD partners
- Dr Samantha Knight
- Dr Jenny Taylor
- Dr Jamie Bentham
- Prof Chris Holmes
- Prof Martin Farrall
- Prof Bernard Keavney, Newcastle
- Prof Judith Goodship, Newcastle
- Prof David Brook, Nottingham
- Dr Frances Bu'Lock, Nottingham
- Dr David Winlaw, Sydney
- Prof Mark Lathrop, CNG
- Prof Koenraad Devriendt, Leuven
- Bentham Jamie and Bhattacharya Shoumo (2008) Genetic mechanisms controlling cardiovascular development. Ann N Y Acad Sci, 1123:10-9.
- MacDonald Simon T, Bamforth Simon D, Chen Chiann-Mun, Farthing Cassandra R, Franklyn Angela, Broadbent Carol, Schneider Jurgen E, Saga Yumiko, Lewandoski Mark, and Bhattacharya Shoumo (2008) Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovasc Res, 79(3):448-57.
- Szumska Dorota, Pieles Guido, Essalmani Rachid, Bilski Michal, Mesnard Daniel, Kaur Kulvinder, Franklyn Angela, El Omari Kamel, Jefferis Joanna, Bentham Jamie, Taylor Jennifer M, Schneider Jurgen E, Arnold Sebastian J, Johnson Paul, Tymowska-Lalanne Zuzanna, Stammers Dave, Clarke Kieran, Neubauer Stefan, Morris Andrew, Brown Steve D, Shaw-Smith Charles, Cama Armando, Capra Valeria, Ragoussis Jiannis, Constam Daniel, Seidah Nabil G, Prat Annik, and Bhattacharya Shoumo (2008) VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev, 22(11):1465-77.
- Bhattacharya Shoumo, Macdonald Simon T, and Farthing Cassandra R (2006) Molecular mechanisms controlling the coupled development of myocardium and coronary vasculature. Clin Sci (Lond), 111(1):35-46.
- Bamforth Simon D, Braganca Jose, Farthing Cassandra R, Schneider Jurgen E, Broadbent Carol, Michell Anna C, Clarke Kieran, Neubauer Stefan, Norris Dominic, Brown Nigel A, Anderson Robert H, and Bhattacharya Shoumo (2004) Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway. Nat Genet, 36(11):1189-96.
We are studying the genetic mechanisms in cardiogenesis and the requirement of cardiogenetic pathways in adult cardiac remodelling. These pathways are important in the pathogenesis of congenital heart disease, and in maintaining myocardial homeostasis in response to neurohumoral stress. A major focus of the laboratory is to understand the requirement of the transcription factor Cited2, and target transcription factors such as polycomb and Tbx1 in the above processes. To recover novel cardiogenetic mutations, we are using mutagenesis in model organisms together with high-throughput magnetic resonance imaging (MRI, see figure) and high-resolution episcopic microscopy (HREM). We are also using genome wide-association studies and exon re-sequencing in congenital heart disease patients (see GO-CHD study). Our mutagenesis studies have identified a cardiogenetic protease network (proprotein convertases and tolloid-like proteases) that in addition to being required in cardiovascular development, also plays a major role in myocardial remodelling & fibrosis. To understand the molecular function of this network we are using protein interaction approaches in mammalian cells and genetic approaches in drosophila, where this protease network is conserved.
Abnormal cardiogenesis during embryonic development and failure to maintain myocardial homeostasis in adults results, respectively, in congenital heart disease and heart failure, both common and serious disorders. There is growing evidence that genes required for cardiogenesis are also required to maintain myocardial cell number and function, and that neurohumoral mechanisms in heart failure interact with genetic variants to affect myocardial function.
Genetic determinants of cardiogenesis
We are using a combination of mutagenesis in model organisms together with magnetic resonance imaging to identify genes that are required for cardiogenesis. We have recently incorporated a new approach - high resolution episcopic microscopy - into these studies. The genes identified will be systematically tested for their requirement in myocardial homeostasis, in response to neurohumoral stress. They will also be candidates for resequencing in patients with congenital heart disease.
Transcription factor networks in cardiogenesis and myocardial homeostasis
We have established a cardiogenetic transcription factor network consisting of the histone acetyltransferases EP300 and CREBBP, the transcription coactivator Cited2 and the transcription factor TFAP2. Targets of this network are the Nodal-Pitx2c left right patterning pathway, the polycomb genes (Bmi1, Mel18 and Rnf2) which form the PRC1 histone ubiquitylating complex, and the transcription factor Tbx1. This network of genes, in part, controls mesodermal patterning and cell specialisation. Our ongoing projects are to define the role of this network in maintaining myocardial homeostasis in response to neurohumoral stress, and to determine the molecular mechanisms and protein interactions that regulate this network.
Protease networks in cardiogenesis and myocardial homeostasis
Our mutagenesis studies have identified a protease network (consisting of the proprotein convertases Pcsk5, Furin and Pcs6 and the tolloid-like metalloproteinase Tll1) that controls cardiac, vascular and lymphatic development. The proprotein convertases function by cleaving or enhancing the degradation of secretory proproteins including receptors. The tolloid-like metalloproteinases also cleave several secreted proteins such as procollagens, CHRD, HSPG2, and LTBP1, which are important for cardiac development, myocardial remodelling and fibrosis. This protease network and its role in cardiac development is also well conserved in drosophila. We are using cre-lox approaches in model organisms to define the tissue specific requirements of some of these genes in heart development and in myocardial homeostasis. We are also using protease biosensors and genetic approaches in drosophila to address the in vivo regulation of this network, and developing approaches such as LUMIER and split-renilla protein complementation to identify molecular interactors and substrates.
Genetic architecture of congenital heart disease
Approximately ~8% of CHD is inherited in Mendelian fashion, with the rest being sporadic. Major mechanisms of sporadic CHD include chromosomal causes such as Trisomy 21 and 22q11 deletion, which account for approximately 12%. Non-synonymous point mutations in cardiac developmental genes have also been found in case-control candidate gene association studies. We are investigating the genetic architecture in patients with CHD, using a combination of exon-resequencing of candidate genes, genome-wide association studies and array comparative genomic hybridisation approaches. We have developed a national network (the GO-CHD study) for recruiting patients to these studies. We are also developing approaches to translate these discoveries to clinical care in the NHS.