Dr Alasdair MacKenzie
2009-present; 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.
Regulatory Variation, Epigenetics and Human Disease.
It has been demonstrated that up to 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 depression, obesity, alcohol abuse and inflammatory diseases such as arthritis.
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, alcohol intake and inflammatory pain.
We have also learned how to manipulate the activity of these cis-regulatory 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.
Recently we have made a major breakthrough in our use of CAS9/CRISPr technology which has allowed us to selectively knock out these cis-regulatory regions within mice within a matter of weeks. Using QrtPCR and In-situ hybridisation we subsequently demonstrated that these CRISPr cis-regulatory deletions had a significant effect on the mRNA expression of the nearest genes. 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 in Expert Reviews in Molecular Medicine and can be accessed here.
Elizabeth Hay; PhD student funded by Medical Research Scotland and GW Pharmaceuticals to study the effects of genetic and epigenetic modification on the regulation of the CNR1 gene that encodes the cannabinnoid receptor gene.
Andrew McEwan. Post-doc who is funded by the BBSRC to explore the effects of genetic variation and epigenetic modification on the activity of the GAL5.1 enhancer region. Andrew will use a combination of CRISPR based modification of the GAL5.1 enhancer and analysis of alcohol and fat intake in these genome editied mice.
Yvonne Turnbull. MRC funded technician with expertise in in-situ hybridisation, PCR and analysis of CRISPR deletion mouse lines.
Exploring the effects of gene regulatory variation and epigenetic modification on susceptibility to conditions such as depression, chronic inflammatory pain, alcohol abuse and obesity.
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 Prof Mirela Delibegovic and Dr. Chris Murgatroyd (Manchester Metropilitan 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 Sept 2019.
We also have an active collaboration with Prof Roger Pertwee to understand the effects of regulatory polymorphisms on the expression of the cannibinoid receptor gene which is funded by Medical Research Scotland and GW Pharmaceuticals .
Ongoing and productive collaborations have also been established with Dr. Andrew Starkey who, together with Dr. Scott Davidson, have carried out whole genome comparitive analysis of SNP distribution in the human genome. They have also developed novel algorithms to predict the effects of human polymorphisms on the binding of transcription factors.
My lab has also developed fruitful collaborations with Dr Perry Barrett and Prof Julian Mercer at the Rowett Institute where we are collaborating to understand the role galanin gene regulation in appetite control.
Collaborations have been established with Prof John Quinn at the University of Liverpool and Prof Peter McGuffin, Dean of the Institute of Psychiatry at Kings College London. These collaborations were funded by the MRC and were to study the effects of common human polymorphisms on the regulation of genes associated with major depressive disorder.
Funding and Grants
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.
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.
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The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high-fat dietCellular and Molecular Life Sciences, vol. 78, no. 6, pp. 3045-3055Contributions to Journals: Articles
Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?International Journal of Molecular Sciences, vol. 21, no. 21, 7856Contributions to Journals: Articles
Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4Nutritional Neuroscience, vol. 23, no. 4, pp. 321-334Contributions to Journals: Articles
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intakeMolecular Psychiatry, pp. 1-14Contributions to Journals: Articles
Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogeneticsHuman Mutation, vol. 41, no. 1, pp. 291-298Contributions to Journals: Articles
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intakebioRxivContributions to Journals: Articles
Early and reversible changes to the hippocampal proteome in mice on a high-fat dietNutrition and Metabolism, vol. 16, no. 1, 57Contributions to Journals: Articles
Disruption of an enhancer associated with addictive behaviour within the cannabinoid receptor-1 gene suggests a possible role in alcohol intake, cannabinoid response and anxiety-related behaviourPsychoneuroendocrinology, vol. 109, pp. 104407Contributions to Journals: Articles
An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genomeNeuropeptides, vol. 64, pp. 101-107Contributions to Journals: Articles
Neuropeptides-2015, Aberdeen University, ScotlandNeuropeptides, vol. 64, pp. 1Contributions to Journals: Articles