Bhattacharya Group

Research Overview

We are studying the genetic mechanisms controlling cardiogenesis and congenital heart disease. We have used two major approaches: protein interaction and knockout studies to identify transcriptional networks, and random ENU mutagenesis in model organisms together with high-throughput magnetic resonance imaging (MRI, see figure) to identify novel genes involved in cardiogenetic signalling networks. We are also using genome wide-association studies and exon re-sequencing in congenital heart disease patients to identify novel cardiac developmental genes.

A second interest in the lab is to identify genetic interactions and pathways in cell-based high-throughput and high-content screening approaches using siRNA and small molecules. These interactions may help us understand how genes interact to produce complex phenotypes, how the effects of genetic mutation can be buffered, and help us isolate novel druggable targets.

Key Publications

Bhattacharya, S., Michels, C.L., Leung, M.K., Arany, Z.P., Kung, A.L. & Livingston, D.M. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13, 64-75 (1999). PMID: 9887100

Bamforth, S., Braganca, J., Eloranta, J.J., Murdoch, J.N., Marques, F.I.R., Kranc, K.R., Farza, H., Henderson, D.J., Hurst, H.C. & Bhattacharya, S. Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nature Genet 29(4):469-74 (2001). PMID: 11694877

Kranc, K.R., Bamforth, S.D., Braganca, J., Norbury, C., van Lohuizen, M. & Bhattacharya, S. Transcriptional co-activator Cited2 induces Bmi1 and Mel18, and controls fibroblast proliferation via INK4a/ARF. Mol Cell Biol 23, 7658-7666 (2003). PMID: 14560011

Bamforth, S.D., Braganca, J., Farthing, C.R., Schneider, J.E., Broadbent, C., Michell, A.C., Clarke, K., Neubauer, S., Norris, D., Brown, N.A., Anderson, R.A. & Bhattacharya, S. Cited2 controls left-right patterning and heart development through a Nodal–Pitx2c pathway. Nature Genet 36:1189- 1196 (2004). PMID: 15475956

Schneider, J.E., Bose, J, Bamforth, S.D., Gruber, A.D., Broadbent, C., Clarke, C., Neubauer, S., Lengeling, A., & Bhattacharya., S. Identification of cardiac malformations in mice lacking Ptdsr using a novel high-throughput magnetic resonance imaging technique. BMC Dev Biol. 2004 Dec 22;4:16. PMID: 15615595

MacDonald, S.T., Bamforth, S.D., Chen, C.-M., Farthing, C.R., Franklyn, A., Broadbent, C., Schneider, J.E., Saga, Y., Lewandoski, M. & Bhattacharya, S. Epiblastic Cited2 deficiency results in cardiac phenotypic heterogeneity and provides a mechanism for haploinsufficiency. Cardiovasc Res. 2008 Aug 1;79(3):448-57. PMID: 18440989

Szumska, D., Pieles, G., Essalmani, R., Bilski, M., Mesnard, D., Kaur, K., Franklyn, A., El-Omari, K., Jefferis, J., Bentham, J., Taylor, J.M., Schneider, J., Arnold, S.J., Johnson, P., Tymowska-Lalanne, Z., Stammers, D., Clarke, K., Neubauer, S., Morris, A., Brown, S., Shaw-Smith, C., Cama, A., Capra, V., Ragoussis, J., Constam, D., Seidah, N.G., Prat, A. & Bhattacharya, S. VACTERL / Caudal Regression / Currarino Syndrome like malformations in mice with mutation in the proprotein convertase Pcsk5 Genes Dev. 2008 Jun 1;22(11):1465-77. PMID: 18519639

Bentham, J., Michell, A.C., Lockstone, H., Andrew, D., Schneider, J.E., Brown, N.A. & Bhattacharya, S. Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects. Human Molecular Genetics 19, 3394-401 (2010). PMID: 18375573.

Key Reviews

Bhattacharya S & Ratcliffe PJ. ExCITED about HIF. Nature Struct Biol 10: 501-503 (2003). PMID: 12825087

Schneider, J. & Bhattacharya, S. Making the mouse embryo transparent: Identifying developmental malformations using magnetic resonance imaging. Birth Defects Research (Part C) 72:241–249 (2004). PMID: 15495185

Bhattacharya, S., MacDonald S.T. & Farthing, C. Molecular mechanisms controlling the coupled development of myocardium and coronary vasculature. Clin Sci (Lond) 111: 35-46 (2006) PMID: 16764556

Bentham, J. & Bhattacharya S. Genetic Mechanisms Controlling Cardiovascular Development. Ann NY Acad Sci 1123:10-19 (2008). PMID: 18375573

Funding Sources

Wellcome Trust, British Heart Foundation, EU-FP7, Oxford Biomedical Research Centre

Keywords

Congenital heart disease, Heart development, Left-Right patterning, Myocardial Homeostasis

Research Area(s)

Cardiovascular disease