Dr Alasdair MacKenzie

Dr Alasdair MacKenzie

Reader

Overview
Dr Alasdair MacKenzie
Dr Alasdair MacKenzie

Contact Details

Telephone
work +44 (0)1224 437380
Email
Address
The University of Aberdeen Room 2.31, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD.

Biography

  • 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. 
     


 

 

Research

Research Overview

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.

Current Staff;

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.

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 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.

Active collaborations are also maintained with Prof, Andy Russo of the University of Iowa to understand the regulation of the CGRP gene in migraine.

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.

Research Funding and Grants

Research Funding

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

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 Honours genetics option 2(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.

Publications

Publications 

Currently viewing:
Filter by Publication Type

Page 1 of 1 Results 1 to 48 of 48

  • The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high-fat diet

    McEwan, A., Erickson, J. C., Davidson, C., Heijkoop, J., Turnbull, Y., Delibegovic, M., Murgatroyd, C., MacKenzie, A.

    Cellular and Molecular Life Sciences

    Contributions to Journals: Articles

  • 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.

    Nutritional Neuroscience, vol. 23, no. 4, pp. 321-334

    Contributions to Journals: Articles

  • 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., MacKenzie, A.

    Molecular Psychiatry

    Contributions 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 pharmacogenetics

    Hay, E. A., Cowie, P., McEwan, A. R., Ross, R., Pertwee, R. G., MacKenzie, A.

    Human Mutation, vol. 41, no. 1, pp. 291-298

    Contributions to Journals: Articles

  • CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol 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., MacKenzie, A.

    bioRxiv

    Contributions to Journals: Articles

  • Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

    McLean, F. H., Campbell, F. M., Sergi, D., Grant, C., Morris, A. C., Hay, E. A., MacKenzie, A., Mayer, C., Langston, R. F., Williams, L. M.

    Nutrition and Metabolism, vol. 16, no. 1, 57

    Contributions 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 behaviour

    Hay, E. A., McEwan, A., Wilson, D., Barrett, P., D'Agostino, G., Pertwee, R. G., MacKenzie, A.

    Psychoneuroendocrinology, vol. 109, pp. 104407

    Contributions to Journals: Articles

  • An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome

    Hay, E. A., Khalaf, A. R., Marini, P., Brown, A., Heath, K., Sheppard, D., MacKenzie, A.

    Neuropeptides, vol. 64, pp. 101-107

    Contributions to Journals: Articles

  • Neuropeptides-2015, Aberdeen University, Scotland

    MacKenzie, A., Pinter, E., Quinn, J.

    Neuropeptides, vol. 64, pp. 1

    Contributions to Journals: Articles

  • Determining Epigenetic Targets: A Beginner's Guide to Identifying Genome Functionality Through Database Analysis

    Hay, E. A., Cowie, P., MacKenzie, A.

    Methods in Molecular Biology, vol. 1589, pp. 29-45

    Contributions to Journals: Articles

  • The noncoding human genome and the future of personalised medicine

    Cowie, P., Hay, E. A., MacKenzie, A.

    Expert Reviews in Molecular Medicine, vol. 17, e4

    Contributions to Journals: Articles

  • Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes

    Richardson, T. G., Minica, C., Heron, J., Tavare, J., MacKenzie, A., Day, I., Lewis, G., Hickman, M., Vink, J. M., Gelernter, J., Kranzler, H. R., Farrer, L. A., Munafò, M., Wynick, D.

    American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, vol. 165, no. 8, pp. 654-664

    Contributions to Journals: Articles

  • Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

    Hay, C., Shanley, L., Davidson, S., Cowie, P., Lear, M., McGuffin, P., Riedel, G., McEwan, I. J., MacKenzie, A.

    Psychoneuroendocrinology, vol. 47, pp. 43-55

    Contributions to Journals: Articles

  • In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling

    Fowler, P. A., Childs, A. J., Courant, F., MacKenzie, A., Rhind, S. M., Antignac, J., Le Bizec, B., Filis, P., Evans, F., Flannigan, S., Maheshwari, A., Bhattacharya, S., Monteiro, A., Anderson, R. A., O'Shaughnessy, P. J.

    Human Reproduction, vol. 29, no. 7, pp. 1471-1489

    Contributions to Journals: Articles

  • Allele-specific differences in activity of a novel cannabinoid receptor 1 (CNR1) gene intronic enhancer in hypothalamus, dorsal root ganglia, and hippocampus

    Nicoll, G., Davidson, S., Shanley, L., Hing, B., Lear, M., McGuffin, P., Ross, R., MacKenzie, A.

    The Journal of Biological Chemistry, vol. 287, no. 16, pp. 12828-12834

    Contributions to Journals: Articles

  • Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism

    Davidson, S., Lear, M., Shanley, L., Hing, B., Baizan-Edge, A., Herwig, A., Quinn, J. P., Breen, G., McGuffin, P., Starkey, A., Barrett, P., Mackenzie, A.

    Neuropsychopharmacology, vol. 36, no. 11, pp. 2211-2221

    Contributions to Journals: Articles

  • Genome-wide association study of major recurrent depression in the U.K. population

    Lewis, C. M., Ng, M. Y., Butler, A. W., Cohen-Woods, S., Uher, R., Pirlo, K., Weale, M. E., Schosser, A., Paredes, U. M., Rivera, M., Craddock, N., Owen, M. J., Jones, L., Jones, I., Korszun, A., Aitchison, K. J., Shi, J., Quinn, J. P., MacKenzie, A., Vollenweider, P., Waeber, G., Heath, S., Lathrop, M., Muglia, P., Barnes, M. R., Whittaker, J. C., Tozzi, F., Holsboer, F., Preisig, M., Farmer, A. E., Breen, G., Craig, I. W., McGuffin, P.

    American Journal of Psychiatry, vol. 167, no. 8, pp. 949-957

    Contributions to Journals: Articles

  • Long-Range Regulatory Synergy Is Required to Allow Control of the TAC1 Locus by MEK/ERK Signalling in Sensory Neurones

    Shanley, L., Davidson, S., Lear, M., Thotakura, A. K., McEwan, I. J., Ross, R. A., Mackenzie, A.

    Neuro-Signals, vol. 18, no. 3, pp. 173-185

    Contributions to Journals: Articles

  • Evidence of uneven selective pressure on different subsets of the conserved human genome: implications for the significance of intronic and intergenic DNA

    Davidson, S., Starkey, A., MacKenzie, A.

    BMC Genomics, vol. 10, 614

    Contributions to Journals: Articles

  • Prediction and characterisation of a highly conserved, remote and cAMP responsive enhancer that regulates Msx1 gene expression in cardiac neural crest and outflow tract

    Miller, K. A., Davidson, S., Liaros, A., Barrow, J., Lear, M., Heine, D., Hoppler, S., MacKenzie, A.

    Developmental Biology, vol. 317, no. 2, pp. 686-694

    Contributions to Journals: Articles

  • A highly conserved Wnt-dependent TCF4 binding site within the proximal enhancer of the anti-myogenic Msx1 gene supports expression within Pax3-expressing limb bud muscle precursor cells

    Miller, K. A., Barrow, J., Collinson, J. M., Davidson, S., Lear, M., Hill, R. E., MacKenzie, A.

    Developmental Biology, vol. 311, no. 2, pp. 665-678

    Contributions to Journals: Articles

  • Generation of a transgenic model to address regulation and function of the human neurokinin 1 receptor (NK1R)

    Vasiliou, A. S., MacKenzie, A., Morris, R., McLaughlin, L., Bubb, V. J., Haddley, K., Quinn, J. P.

    Neuropeptides, vol. 41, no. 4, pp. 195-205

    Contributions to Journals: Articles

  • Evidence for Glucocorticoid Mediated Regulation of Substance P Expression in the Amygdala: A Possible Mechanistic Link Between Chronic Stress and Anxiety

    Barrow, J., MacKenzie, A.

    Contributions to Conferences: Papers

  • Closing the systems biology validation gap – comparative genomics and depressive disease

    Barrow, J., Davidson, S., Lear, M., MacKenzie, A.

    Cold Spring Harbor Laboratory/Wellcome Trust Conference on Functional Genomics and Systems Biology

    Contributions to Conferences: Posters

  • Postgenomic bioinformatic analysis of yeast artificial chromosome sequence

    Miller, K. A., Davidson, S., MacKenzie, A.

    YAC Protocols. MacKenzie, A. (ed.). 2 edition. Humana Press, pp. 41-59, 349 pages

    Chapters in Books, Reports and Conference Proceedings: Chapters

  • Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice

    Lang, B., Song, B., Davidson, W., MacKenzie, A., Smith, N., McCaig, C. D., Harmar, A. J., Shen, S.

    The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1924-1934

    Contributions to Journals: Articles

  • Transcription Factor-DNA Interactions at the Substance P Enhancer, ECR1

    Barrow, J., MacKenzie, A.

    Mechanisms Underlying Emerging Themes in Neurobiology

    Contributions to Conferences: Abstracts

  • Purification and Characterisation of a Population of EGFP-Expressing Cells from the Developing Pancreas of a Neurogenin3/EGFP Transgenic Mouse

    Barrow, J., Bernardo, A. S., Blaylock, M. G., Duncan, L., MacKenzie, A., McCreath, K., Kind, A. J., Schnieke, A. E., Colman, A., Hart, A. W., Docherty, K.

    Contributions to Conferences: Posters

  • Purification and characterisation of a population of EGFP- expressing cells from the developing pancreas of a neurogenin3/EGFP transgenic mouse.

    Barrow, J., Bernardo, A., Blaylock, M., Duncan, L., MacKenzie, A., McCreath, K., Kind, A. J., Schneike, A., Colman, A., Hart, A. W., Docherty, K.

    Organogenesis, vol. 2, pp. 22-27

    Contributions to Journals: Articles

  • Is there a functional link between gene interdigitation and multi-species conservation of synteny blocks?

    MacKenzie, A., Miller, K. A., Collinson, J. M.

    BioEssays, vol. 26, no. 11, pp. 1217-1224

    Contributions to Journals: Articles

  • Post-genomic approaches to exploring neuropeptide gene mis-expression in disease

    MacKenzie, A., Quinn, J.

    Neuropeptides, vol. 38, no. 1, pp. 1-15

    Contributions to Journals: Articles

  • Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransduction

    Millward-Sadler, S. J., MacKenzie, A., Wright, M. O., Lee, H. S., Elliott, K., Gerrard, L., Fiskerstrand, C. E., Salter, D. M., Quinn, J. P.

    Arthritis & Rheumatism, vol. 48, no. 1, pp. 146-156

    Contributions to Journals: Articles

  • A yeast artificial chromosome containing the human preprotachykinin-A gene expresses substance P in mice and drives appropriate marker-gene expression during early brain embryogenesis

    MacKenzie, A., Quinn, J.

    Molecular and Cellular Neuroscience, vol. 19, no. 1, pp. 72-87

    Contributions to Journals: Articles

  • A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo

    MacKenzie, A., Quinn, J.

    PNAS, vol. 96, no. 26, pp. 15251-15255

    Contributions to Journals: Articles

  • Two enhancer domains control early aspects of the complex expression pattern of Msx1

    MacKenzie, A., Purdie, L., Davidson, D., Collinson, M., Hill, R. E.

    Mechanisms of Development, vol. 62, no. 1, pp. 29-40

    Contributions to Journals: Articles

  • Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape.

    MacKenzie, A., Ferguson, M., Sharpe, P. T.

    Development, vol. 115, no. 2, pp. 403-420

    Contributions to Journals: Articles

  • Hox-7 expression during murine craniofacial development

    MacKenzie, A., Ferguson, m., Sharpe, P. T.

    Development, vol. 113, no. 2, pp. 601-611

    Contributions to Journals: Articles

  • The homeobox gene Hox 7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro

    MacKenzie, A., Leeming, G., Jowett, A., Ferguson, M.

    Development, vol. 111, no. 2, pp. 269-285

    Contributions to Journals: Articles

Show 10 | 25 | 50 | 100 results per page