I-MOTIFS: THE RELATIONSHIP BETWEEN SEQUENCE, STRUCTURE AND FUNCTION

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C-rich regions of DNA can form alternative secondary structures called i-motifs, which have not only shown utility as bio-compatible pH-responsive materials in nanotechnology, but also have been shown to exist and act as molecular switches in cells. Although there have been significant advances in this area, we are still yet to understand their prevalence in the human genome and extent of their roles in biology.

Our hypothesis is that iM structures form in vivo but natural mutations will affect the function of these structures and could result in age-related diseases and conditions. The project will test this using a range of bioinformatic, biological, biophysical and molecular biology techniques.

In this proposal, we will test the importance of the structural features in i-motif and their effect on biological function using cell-based reporter gene assays. We will systematically mutate cytosines and loops out of the sequence of interest and correlate between the underlying C-rich sequence, resulting structure and gene function. The proposal aims to reveal the global presence of i-motifs in cells. This will involve developing a method, based on similar principles to SHAPE chemical probing in RNA and G-quadruplex-seq methods. It will reveal the presence of i-motif structures and can be able to be applied in vitro, in cells or in vivo to any organism. We will bring together the new understanding of i-motifs to investigate the effects of ageing on these structures, their potential changes in function and how this may play a role in age-related diseases and conditions.