Professor Alasdair MacKenzie

Biography

• 2021-present: Personal Chair, University of Aberdeen
• 2009-2021; Reader, University of Aberdeen.
• 2006-2009; Senior Lecturer, University of Aberdeen.
• 2001-2006; Lecturer, University of Aberdeen.
• 1997-2001;Postdoc. University of Edinburgh Vet School.
• 1992-1997;Postdoc. MRC Human Genetics Unit, Edinburgh.
• 1992-Manchester University, Ph.D. in Molecular and Cellular Biology.
• 1989-University of Strathclyde BSc.(Hons)in Cell Biology. 
   
  
  
  

Research Overview

Regulatory Variation, Epigenetics and Human Disease.

 Over 95% of the genetic differences that have been associated with disease are found outside of genes. We are interested in finding out how these genetic differences, also known as polymorphisms, within the human genome, can change where, when and by how much neuropeptide genes are activated within the human nervous system. We are particularly interested in the role of gene mis-expression in generating susceptibility to conditions that include anxiety, obesity, and alcohol abuse.

To this end we have used comparative genomics to identify the genetic "switches", or enhancer regions, that control the expression of a number of different genes including substance-P, Brain derived neurotrophic factor (BDNF), the Cannabinoid-1 receptor gene, (CB1) and the galanin gene (GAL) that  play a role in controlling appetite, mood, and alcohol intake. The strength of focussing on enhancer regions conserved in all higher vertebrates is that we can explore the roles of these human enhancers in non-human models using CRISPR-Cas9 technologies. Thus, we have shown that enhancers that are conserved between humans and mice play important roles in dietary choices, ethanol intake and mood when deleted from mice.

In addition to deleting enhancers we have also learned how to humanise enhancers in mouse lines (i.e. replace mouse enhancers with disease associated allelic variants of human enhancers) using AAV and CRISPR mediated technologies.

We have also learned how to manipulate the activity of these enhancer regions and to test the effects of polymorphic variation in transgenic lines and cell lines using a number of different drug treatments. Our studies have shown that disease associated polymorphisms occur in enhancer regions and alter cell specific levels of activity and responses to specific drugs. Subsequent analysis of these enhancer CRISPR deletion mouse lines showed a decrease in fat and alcohol intake as well as evidence of reduced anxiety and drug response. 

In addition to understanding the basis of disease these novel observations hold the key to understanding why some patients fail to respond to certain drug therapies or suffer dangerous side effects. We believe that only by understanding how genetic differences within the human genome lead to disease and differences in drug response can we deliver on the promises of personalised medicine.

Recent studies have shown that epigenetic changes in the form of DNA-methylation also have a major effect on gene regulation by altering the function of promotors and enhancer regions. Levels of methylation at enhancer sequences is affected by environmental events such as early life stress or poor diet. Thus, exploring the effects of epigenetic changes on the functioning of enhancers and promoters represents the next big step our lab is set to take in understanding the interaction of environment and genetics in disease.

A recent review of our novel approaches to understanding regulatory variation and disease has been published as a "State-of-the-art Review" in FEBS Journal and can be accessed here.

Current Research

Exploring the effects of gene regulatory variation and epigenetic modification on susceptibility to conditions such as depression, chronic inflammatory pain, alcohol abuse and obesity.

Collaborations

We actively collaborate with a number of research groups from within the University of Aberdeen as well as groups in the rest of the UK and abroad.

For example, thanks to recent BBSRC project funding we have recently cemented an exciting collaboration with  Dr. Chris Murgatroyd (Manchester Metropolitan University) to study the effects of genetic and epigenetic variation on the regulation of the galanin gene in the hypothalamus. This project will allow us to use CRISPr technologies to push our understanding of fat and alcohol intake until March 2026.

Funding and Grants

Research Funding

BBSRC; How do genetics and epigenetics interact to influence the activity of a context-dependent enhancer? (£720k). A. MacKenzie. C. Murgatroyd and A. McEwan. 2023-2026.

Medical Research Scotland; Determining the biological basis for, and de-stigmatising, problematic alcohol use and anxiety. (£103k). A. MacKenzie, E. Collie-Duguid, W. Gault and J. Mooney 2022-2026.

MRC Discovery@aberdeen.: A novel in-vivo CRISPR enhancer screen to identify polymorphic regulatory regions controlling the hypothalamic expression of appetite regulating neuropeptides. A. McEwan and A. MacKenzie (£25k).

BBSRC; Determining the effects of genetic variation and early life stress on the regulation of the galanin gene in fat and alcohol selection. A. MacKenzie, M. Delibegovic, C. Murgatroyd, S. Davidson. 2016-2019. (£515k).

GW Pharmaceuticals; Effect of genetic & drug epigenetic variation on the control on the CB1 gene in disease & drug efficacy. MacKenzie. A and Pertwee, R. 2014-2017 (£10k).

Wellcome trust ISSF fund. A genome editing approach to understanding the regulation of neuropeptides controlling inflammatory pain and appetite. MacKenzie A. 2015-2016 (£20k).

Medical Research Scotland; The effects of genetic and epigenetic variation on the control of the cannabinoid-1 receptor gene and their role in disease and drug efficacy. A. MacKenzie and Roger Pertwee. 2014-2017. £104k.

University of Aberdeen development trust Hotstart Fund; MacKenzie, A., Carrington, A., McCaffery, P., Erskine, L., Fowler, P., Ballal, H., MacFarlane, T. 2010. (£9.8k).

Medical Research Council; Prediction and analysis of a regulatory SNP map of Major Depressive Disorder. A. MacKenzie, J.P. Quinn, G. Breen and Peter McGuffin. 2008-2011. £1,105k

Scottish Executive-CSO Grant; Deregulation of Androgen Receptor Signalling in Prostate Cancer. I. McEwan and A. MacKenzie. 2007-2011, £364k.

Wellcome trust project grant; Predictive genomic and transgenic analysis of tachykinin gene regulatory systems in the amygdala. A.MacKenzie, R.Ross, I.McEwan, G. Riedel. 2007-2010,343k.

BBSRC Research equipment initiative grant; A computer array approach to accelerating the functional prediction of Biological systems. A. MacKenzie, A. Starkey, I. Stansfield, A. Brown, A. Donaldson, A. M. Coghill, D. Ritchie. £93k (46.5 from BBSRC and 46.5k from external sources)

BBSRC project grant; Predictive biology and transgenic analysis of regulatory systems controlling tachykinin expression in sensory neurones. A. MacKenzie, I. J. McEwan, R. Ross and D.MacEwan, 2005-2008, £ 313k.

BBSRC strategic PhD. Research Studentship. In-silico identification of functional gene and regulatory sequence linkage. Alasdair MacKenzie and Andrew Starkey. 2005-2008

Wellcome Trust Programme grant ; Mechanisms of Action for endothelial nitric oxide synthase on bone. Prof. Stuart Ralston, Dr. Miep Heilfrich and Dr. Alasdair MacKenzie, £461k, 2003-2008

ARC Program grant; The Genetics of Pagets Disease, Stuart Ralston, Alasdair MacKenzie, Dave McEwen, Mike Rodgers. £690k, 2003-2008.

Nuffield foundation Oliver Bird Collaborative Centre Grant, 549k, Prof David M Reid, Prof R Aspen, Prof. Mike Rodgers, Dr. Alasdair MacKenzie, Dr. Miep Heilfrich, Dr. H. MacDonald, Dr. M. Plater. 2003-2007.

SHERT, 80k. Cellular and molecular mechanisms of neural tube defects. Sanbing Shen and Alasdair MacKenzie. 2004-2006.

Tenovus Scotland, 10k. Alasdair MacKenzie; The use of mouse-human sequence homology and transgenic technology to detect Preprotachykinin-A cis-regulatory regions 2003-2004.

Tenovus Scotland. 10k. Alasdair MacKenzie; An exploration of the co-expression of different Substance P receptors at the cellular level in the joints, large intestine, lung, dorsal horn and amygdala 2004-2005.

Teaching Responsibilities

I am course co-ordinator for the second year course entitled Molecular Biology of the Gene (BI20M3) as well as co-ordinator of an Honours course entitled Human Functional Genomics (GN4310).

I also teach on GN3502 (Genetics), SM3007 (Frontiers of Molecular Medical sciences),DB3501 (developmental Genetics) and on an MSc course entitled Genome Enabled Medicine (MB5517).

This year I will also teach a series of lectures on the 6th Century Course "Mankind and the Universe" discussing the morality and ethics of some current topical genetics and cell biology subjects.