I am a keen tango dancer. My partner, Angela, and I organise Argentinean Tango events and teach in Tynemouth (www.tango-on-tyne.co.uk). The picture shows us dancing in Switzerland in the cold....
My research focuses on two major areas:
• Gene regulation by natural antisense transcripts
• Epithelial Na/phosphate transport
Natural antisense transcripts (NATs) represent an enigmatic phenomenon seen in all organisms but are increasingly prevalent in mammals. This indicates that NATs are selected for during evolution and have therefore a distinct biological role. Very recent work from our lab provided key evidence for suggesting a comprehensive and generally applicable model of NATs action: Sense and antisense transcripts are co expressed only during a short time period, possibly observed during early (embryonic) stem- or germ cell development. The two transcripts are fully processed to guarantee stability and freedom to diffuse in the nucleus. Both sense and antisense transcripts may form RNA duplexes- or, alternatively, traffic to the cytoplasm. The nuclear RNA hybrids are processed into short RNAs. The short RNAs are transported into the cytoplasm where both the sense and the antisense oriented strands are included into an RNA induced silencing complex. A yet unknown biochemical process that may include RNAi components and the complementary full-length sense or antisense RNA leads the accumulation of either sense or antisense short RNA.
Our results indicate that under physiological conditions the short RNA complementary to the antisense transcripts eventually prevails. Feedback to the transcriptional level will target and silence the antisense promoter.
To understand the biological benefit of the hypothesized model we assume that a protein encoding gene developed a mutation. In the presence of a complementary antisense transcript the gene will be scrutinized via the short RNA pathway. If the mutation reverses the short RNA strand selection the mutated sense transcript becomes silenced and only the second, unmutated copy of the gene stays active. For obvious reasons the proposed mechanism only proves beneficial for an organism if the second allele is functional.
To summarise, we suggest that antisense transcripts help to reduce the impact of mutaions. (The manuscript containing all the relevant data is submitted, further details are also given on the narna webpage: www.narna.ncl.ac.uk)
Inorganic phosphate (Pi)
Inorganic phosphate (Pi) is an essential component in every cell, think of ATP or phosphorylation of proteins, and every organism controls the level of phosphate in its body fluid tightly. Pi is an important component of our diet, we take it up in the intestine and excrete the spare component via the kidney. Different isoforms of a membrane transport protein called NaPi-II are involved in both intestinal absorption and renal excretion. We are particularly interested in two aspects of these proteins. First, we investigate the impact of a protein motive, an extended stretch of cysteine residues in the C-terminus of the transporter, on intracellular protein trafficking. We found that lipid anchors (palmitic acid) are attached to the cysteine stretch. The lipid anchor is indeed crucial for the correct delivery of the transporter to the plasma membrane. Second, we plan to lock at the contribution of specific amino acids to substrate selection (how can the transporter distinguish between the similar ions phosphate and sulphate) and transport efficiency (how does phosphate translocate through the membrane protein). For this purpose we will mutate the phosphate transporter and express it in Xenopus oocytes. We will then measure the transport efficiency and compare the data to unmutated controls. These experiments are performed in collaboration with Dr. Ian Forster at the Institute of Physiology, Zurich, Switzerland.
Figure 1. The core and the C-terminus of the Na/Pi cotransporter are both important for intracellular trafficking in cultured cells (MDCK). Red stains the apical membrane of the cells, green represents the transporter. Yellow indicates and overlay of green and red, hence apical localisation of the transporter.
Qualifications: Teaching degree, Secondary School level (French German, History and PE, Journalism
Coordinator of the international antisense RNA interest group
Biomedical Sciences Course, first year: Respiratory Physiology, Integrative Physiology, Module Leader
Dental Medicine, first year: Respiratory Physiology, Integrative Physiology
Biomedical Sciences Course, third year: RNA biology and Project supervision