• 1616 Citations
1991 …2020

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Personal profile

Biography

Dr MacKenzie graduated from Strathclyde University with a 2.1 degree in Molecular and Cell Biology in 1988 and went on to do a PhD in molecular embryology under the supervision of Prof Paul Sharpe at the Unversity of Manchester where he studied the expression of the Msx1 and Msx2 genes in the craniofacial region and dentition of the developing mouse embryo. During this time Dr MacKenzie succeeded in publishing 3 papers in the high profile journal Development that, together, have accumulated nearly 600 citations. Dr MacKenzie obtained his PhD in 1992 and went on to do his first post-doc at the MRC Human Genome Unit at the Western General Hospital in Edinburgh under the leadership of Prof Robert Hill where he undertook the development of gene knockout models of the Msx1 and Msx2 genes in mice. Two years into this post-doc another laboratory in the US was able to publish a paper describing the effects of Msx1 and 2 knockouts rendering Dr MacKenzies progress in generating these knockouts redundant. However, Dr MacKenzie then went on to develop an understanding of the tissue-specific regulation of the Msx1 gene using transgenic mouse embryos. Based on his expertise of using transgenic analysis to understand tissue specific gene regulation in 1997 Dr MacKenzie went on to do a second post-doc in neuropeptide gene regulation at Edinburgh University under the leadership of Prof John Quinn. During this time Dr MacKenzie published many high profile papers including one on the role of VNTRs in the regulation of the serotonin transporter gene that was published in PNAS and has been cited 421 times to date.  During his time with Prof Quinn Dr MacKenzie also published an article in Arthritis and Rheumatism and optimised the generation of Yeast Artificial Chromosome transgenic mice that resulted in two more publications. In 2001 Dr MacKenzie accepted an offer of a lectureship at the University of Aberdeen where he is currently employed as a reader in molecular genetics. Since coming to Aberdeen Dr MacKenzie has authored or co-authored 30 research publication, many in high profile journals that have included Molecular Psychiatry (2 publications), Neuropsychopharmacology, Journal of Clinical Investigation, American Journal of Psychiatry, Biological Psychiatry, Trends in Molecular Medicine and has been principle applicant or co-applicant on over £3.5 million of grant funding from the Wellcome trust, the BBSRC and the MRC. In 2008 Dr MacKenzie led a succesful MRC funded consortium with a value of £1.3 million with the School of Psychiatry at Kings College London and Liverpool University to study the genetics of major depressive disorder. Most recently, Dr MacKenzie has led a succesfull BBSRC funded collaboration with the University of Edinburgh and Manchester Metropolitan University leading to a major publication in the high profile journal Molecular Psychiatry where a unique combination of human gene association studies and CRISPR genome editing led to the discovery of a tissue specific enhancer region that contributed to increased susceptibility to alcohol abuse and anxiety in men .

Research Interests:

My research interests focus around the effects of non-coding disease associated polymorphisms on the activity of highly conserved enhancer elements that control the tissue specific expression of genes known to be important in health. My primary focus has been on the regulatory elements that support the expression of neuropeptides such as Substance-P and Galanin in regions of the nervous system that include the dorsal root ganglia, the hypothalamus and the amygdala where these peptides are known to regulate the inflammatory response, nutrient selection and mood respectively. More recently, my lab has also studied the effects of regulatory polymorphisms on the regulation of the cannabinoid-1 receptor gene (CNR1) with a view to gaining a better understanding of cannabinoid pharmacogenomics. My approach to identifying and characterising enhancer regions is different to the "mainstream methods" currently favoured which utilise large scale whole genome analysis to detect enhancers using ChIP-seq (H3K4me, H3K27ac, transcription factor binding etc) and DNAse hypersensitivity analysis in cancer cells. Instead, my lab has relied on the hypothesis that because the cell specific expression of genes in regions of the brain such as the hypothalamus has been so highly conserved between species so too have the enhancer regions which support this expression. Thus, we have had considerable success in using comparative genomics to identify a number of tissue specific enhancers. Our research methods also differ from those of the majority of other labs who choose to identify and characterise enhancer regions using next generation sequencing based techniques in cultured cancer cell cultures. Because we recognise the importance of analysing the activity of tissue-specific enhancers within a relevent model system, we have chosen to characterise enhacer activity using either primary cell cultures, that we magnetofect with reporter plasmids, or transgenic reporter mice that permit the activity of cell specific enhancer regions within relevent tissue. Over the past 5 years we have used CRISPR genome editing to delete these enhancer regions in mice that allows analysis of their function in tissue specific gene expression as well as physiology and behaviour within living whole animal models. In addition to these unique in-vivo analyses we have further characterised these enhancers using transformed cell culture systems to validate the protein-DNA interactions that support their actiivity and to explore the effects of disease associated polymorphic variation on this activity/interaction. Most recently, we have initiated experiments in cells and in animal models to explore the effects of environmentally modulated DNA-methylation on the activity of these enhancers and how this methylation is affected by changes in maternal diet or early life stress. 

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Research Output

CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake

McEwan, A. R., Davidson, C., Hay, E., Turnbull, Y., Erickson, J. C., Marini, P., Wilson, D., McIntosh, A., Adams, M. J., Murgatroyd, C., Barrett, P., Delibegovic, M., Clarke, T-K. & MacKenzie, A., 13 Mar 2020, In : Molecular Psychiatry.

Research output: Contribution to journalArticle

  • Open Access
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  • 4 Downloads (Pure)

    Palmitic acid triggers inflammatory responses in N42 cultured hypothalamic cells partially via ceramide synthesis but not via TLR4

    Sergi, D., Morris, A. C., Kahn, D. E., McLean, F. H., Hay, E. A., Kubitz, P., MacKenzie, A., Martinoli, M. G., Drew, J. E. & Williams, L. M., 2020, In : Nutritional Neuroscience. 23, 4, p. 321-334 14 p.

    Research output: Contribution to journalArticle

  • 15 Citations (Scopus)

    CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggest its role in anxiety and male alcohol intake

    Mcewan, A., Hay, E., Davidson, C., Turnbull, Y., Erickson, J., Marini, P., Wilson, D., McIntosh, A. M., Adams, M. J., Murgatroyd, C., Barrett, P., Delibegovic, M., Clarke, T-K. & MacKenzie, A., 13 Dec 2019, In : bioRxiv. 36 p.

    Research output: Contribution to journalArticle

    Open Access
  • Open Access
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  • 5 Citations (Scopus)
    5 Downloads (Pure)

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