Dr Brewer was appointed Senior Lecturer at King’s College London in September 2015 and is a Principle Investigator in Cardiovascular Biology. She graduated from Cambridge University with a BA in Natural Sciences (Genetics) in 1981. She completed her PhD in the laboratory of Professor Roger Patient at the Developmental Biology Research Centre, King’s College London in 1995. This was followed by postdoctoral posts with Professors Roger Patient and Farzin Farzaneh in the Randall Division at King’s College London, investigating the roles and regulation of members of the GATA family of transcription factors in blood and heart development.
Current Research Interests
Since moving to the King’s Cardiovascular Division, my interest in transcriptional regulation has extended to investigation of molecular pathways involved in modulating and transducing changes in cellular redox to effect functional phenotypic changes. Under normal physiological conditions, small amounts of Reactive Oxygen Species (ROS), such as superoxide and hydrogen peroxide are generated and utilised by cells to act as “second messengers”, transducing both extra- and intra-cellular cues to regulate cellular responses to physiological changes. A critical source of these signalling ROS in cardiovascular cells and a major focus of my studies has been the family of phagocytic-type NADPH oxidases, termed NOXs. Our studies have demonstrated that ROS generated by one member of this family, NOX4, are important in the homeostatic maintenance of function of both cardiomyocytes and vascular cells in response to physiological stresses. NOX4 is an inducible gene and we have shown its expression to be upregulated, for instance, under hypoxic conditions. As a consequence of this upregulation, increased ROS are produced which act directly or indirectly to switch the function of specific proteins within cells, including redox-sensitive transcription factors. Using in vivo, ex vivo and in vitro approaches we have demonstrated specific roles for NOX4-generated ROS in the modulation of transcriptional expression patterns which drive cardiomyocyte differentiation1, cell cycling2, hypertrophy3 and endothelial cell-dependent regulation of vascular tone4,5.
Transcriptional Regulation by Epigenetic Mechanisms
Another exciting, more recent, field of investigation is the regulation of epigenetics by redox-dependent mechanisms. Methylation of both histone proteins and the genomic DNA itself plays a major role in transcriptional control of gene expression. Intriguingly, the activities of the enzymes which remove such epigenetic methylation marks can be altered by changes in cellular redox, and by changes in oxygen availability and some specific metabolites. We have begun to investigate the role of these epigenetic modulators as “sensors” of such changes in normal physiological processes. We have shown that the activities of the Ten-Eleven Translocase (TET) proteins, which remove methyl groups from DNA are sensitive to graded levels of oxygen which are of physiological relevance within the early mammalian embryo and may be important in determining cell fate6. We are now currently also investigating whether the dysregulation of these TET proteins under hyperglycaemic conditions might account in part for the epigenetic changes known to be associated with cardiovascular dysfunction that is common in diabetic patients.
1. Murray TV, Smyrnias I, Shah AM, Brewer AC. Nadph oxidase 4 regulates cardiomyocyte differentiation via redox activation of c-jun protein and the cis-regulation of gata-4 gene transcription. J Biol Chem. 2013;288:15745-15759
2. Murray TV, Smyrnias I, Schnelle M, Mistry RK, Zhang M, Beretta M, Martin D, Anilkumar N, de Silva SM, Shah AM, Brewer AC. Redox regulation of cardiomyocyte cell cycling via an erk1/2 and c-myc-dependent activation of cyclin d2 transcription. J Mol Cell Cardiol. 2015;79:54-68
3. Zhang M*, Brewer AC*, Schroder K*, Santos CX, Grieve DJ, Wang M, Anilkumar N, Yu B, Dong X, Walker SJ, Brandes RP, Shah AM. Nadph oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci U S A. 2010;107:18121-18126
4. Ray R, Murdoch CE, Wang M, Santos CX, Zhang M, Alom-Ruiz S, Anilkumar N, Ouattara A, Cave AC, Walker SJ, Grieve DJ, Charles RL, Eaton P, Brewer AC*, Shah AM*. Endothelial nox4 nadph oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol. 2011;31:1368-1376
5. Mistry RK, Murray TV, Prysyazhna O, Martin D, Burgoyne JR, Santos C, Eaton P, Shah AM, Brewer AC. Transcriptional regulation of cystathionine-gamma-lyase in endothelial cells by nadph oxidase 4-dependent signaling. J Biol Chem. 2016;291:1774-1788
6. Burr S, Caldwell A, Chong M, Beretta M, Metcalf S, Hancock M, Arno M, Balu S, Kropf VL, Mistry RK, Shah AM, Mann GE, Brewer AC. Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of tet activity in embryonic stem cells. Nucleic Acids Res. 2018;46:1210-1226
* Joint authors