Dr Andrew Mcewan
A novel in-vivo CRISPR enhancer screen to explore the role of polymorphic regulatory regions in the control of hypothalamic neuropeptide expression.
Understanding the biological basis of obesity is one of the major current priorities in medicine. By combining the use of comparative genomics, CRISPR genome editing, transcription analysis and analysis of feeding behaviour we will explore the role of hypothalamic neuropeptide gene expression in appetite regulation. Expression of genetic material is a finely orchestrated process; 10 years of genetic research strongly indicates that changes in the genomic mechanisms that ensure correct gene expression may influence susceptibility to conditions such as obesity and alcoholism. Regions of the genome (known as enhancers) are understood to control the expression of genes needed to modulate for example fat and alcohol intake; in addition to making normal proteins, genes have to be expressed in the right cells, in appropriate amounts and in response to the correct signals to ensure health. Gene editing technologies (such as the CRISPR-CAS9 system) can now be used to rapidly alter the genome of model organisms allowing us to more efficiently characterise expression than ever before. In the MRC-Discovery funded project Dr McEwan and his colleagues are at the cutting edge of using such technologies. NPY and BDNF will be targeted as they are two genes of particular interest since they are known to influence food selection and intake. Exploring their regulation by these novel approaches will lead to important insights into how genetic and epigenetic variation in the human genome may influence gene expression and how dysregulation may lead to exacerbating our susceptibility to excess calorie intake and obesity.