Our research focuses on the regulation of mRNA synthesis by RNA polymerase II (RNAP II) in eukaryotic cells. The process of transcription - the synthesis of RNA from a DNA template - is the first step leading to gene expression and is the primary step at which gene expression is regulated. Transcription regulation plays a key role in the control of cell growth, cell differentiation, development and in the response of cells to environmental stimuli and stress. Aberrant transcription is a major cause for disease, including forms of cancer. We use a combination of biochemistry, molecular and cell biology approaches to elucidate at the molecular level the precise mechanisms through which the cellular RNAP II transcription machinery and regulatory factors control transcription.
The two main research interests in the laboratory are:
(i) The role of core promoter sequence information in the regulation of human RNAP II transcription.
The core promoter region of genes transcribed by eukaryotic RNAP II encompasses the transcription start site and can contain a number of different core promoter sequence elements, which direct the site and rate of transcription initiation and modulate the response of the RNAP II transcription machinery to transcription regulators. The classic textbook model of transcription initiation by RNAP II is based on seminal studies using TATA box-containing model promoters. However, only a small fraction (≤ 20%) of genes in the human genome contain a TATA box and the role of core promoter elements other than TATA in directing RNAP II transcription is insufficiently understood.
(ii) Regulation of RNAP II transcription in the malaria parasite Plasmodium falciparum.
The life cycle of Plasmodium in the human host involves several different intracellular asexual and sexual stages, brought about by stage-specific coordinated changes in gene expression patterns. The genome of Plasmodium falciparum is extremely (A+T)-rich, in particular in intergenic regions containing gene promoters, which can contain more than 90% (A+T). Bioinformatics studies suggest that Plasmodium falciparum basic RNAP II transcription machinery components differ significantly in primary structure from their human counterparts. These observations point to the existence of Plasmodium-specific transcription regulatory mechanisms, which could be exploited to develop novel anti-malarial medicines.
Past 3rd year projects:
2012 Cloning and expression of general RNA polymerase II transcription factor TFIIB from Plasmodium falciparum, the causative agent of malaria.
2011 Cloning and expression of general RNA polymerase II transcription factors from Plasmodium falciparum, the causative agent of malaria.