Research Biographies

DR RICHARD MEEHAN

Chromosomes and Gene Expression

Programme Leader

Contact Details

E-mail address:	richard.meehan@igmm.ed.ac.uk
Telephone:	+44 (0)131 332 2471
Fax:	+44 (0)131 467 8456
Address:	MRC Human Genetics Unit MRC IGMM, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU
Research Programme:	Epigenetic Mechanisms in Development and Disease

 

 

Research Areas

Epigenetics, Development and Cancer

I graduated from Trinity College Dublin, Ireland, with a BA degree in Genetics, and obtained my PhD at the MRC Human Geneics Unit, Scotland on the Molecular Genetic Analysis of Hepatic Cytochrome P-450s in mammals (supervised by Dr.'s ND Hastie & CR Wolf). My subsequent postdoctoral research with Dr. Adrian Bird at the IMP, Vienna focused on the characterisation of methyl-CpG binding (MeCP) activities in mammals. This was followed by I.C.R.F. Research Fellowship (with Adrian) at the University of Edinburgh, on the identification of additional MeCP components. We showed that MeCP2 is X-linked in mice and it was subsequently demonstrfated that mutations in the X-linked MECP2 in humans underlie many cases of Rett syndrome, a progressive neurologic developmental disorder, and one of the most common causes of mental retardation in females.

Since starting my lab in 1995 at the Biochemistry Department, George Square, Edinburgh, I have developed Xenopus laevis as a model organism to determine the role of DNA methyltransferases (Dnmts) and MeCPs in development. We made the seminal observation that the maintenance methyltransferase, xDnmt1, is required to maintain transcriptional silencing in pre-mid-blastula transition (MBT) embryos. An enjoyable highlight was work initiated by Irina Stancheva showing that xMeCP2 in Xenopus laevis is required for primary neurogenesis partly through interaction with the SMRT complex, which regulates the activity of xHairy2a, an anti-neurogenic gene. I was also part of a successful collaboration with Lorraine Young and Sir Ian Wilmut, which examined the dynamics of DNA methylation patterns in early in normal and cloned sheep embryos. In contrast to mice and humans, we did not observe preferential demethylation of the paternal genome ovine zygotes. While at George Square I benefited from a classical education in chromatin structure analysis by Jim Allan and Sari Pennings.

I joined the MRC Human Genetics Unit, Edinburgh in 2003, where my lab focuses on molecular mechanisms by which the maintenance cytosine DNA methyltransferase, Dnmt1 and MeCPs mediate gene silencing in early embryos and somatic cells. Recently we identified a non-catalytic transcriptional repressor role for xDnmt1 in early frog development that accounts for gene silencing in pre-MBT embryos. This adds to an intriguing literature that specified non-catalytic roles for DNMT1, which has implications for determining the primary function of DNMT1 in development and disease.
We have just initiated a joint program (headed by Mike Dixon and David Harrison) with colleagues in the HGU (Wendy Bickmore) and CRUK (including Nick Gilbert and Bernie Ramsahoye) that is funded by Breakthrough Breast cancer that will focus on the role of epigenetics and chromatin structure in breast cancer initiation and progression. Recently, I was also a successful co-applicant on a BBSRC grant with colleagues from the QMRI, Dr. Sari Pennings and Professor Sir Ian Wilmut, on investigating how the process of fertilisation initiates the developmental potential of the murine zygote through nuclear remodelling of the compacted genomes of the gametes. We aim to identify the molecular mechanisms of the nuclear reprogramming process leading to the asymmetry in epigenetic marks between the mouse male and female pronucleus.

I am an honoury Senior Lecturer at the University of Edinburgh and an associate member of the epigenome network of excellence www.epigenome-noe.net/.

 

Recent Publications

• Drake AJ, McPherson RC, Godfrey KM, Cooper C, Lillycrop KA, Hanson MA, Meehan RR, Seckl JR, and Reynolds RM. An unbalanced maternal diet in pregnancy associates with offspring epigenetic changes in genes controlling glucocorticoid action and foetal growth. Clin. Endocrinol. (Oxf) 77: 808-815. 2012
  PubMed Abstract
• Katz E, Sims AH, Sproul D, Caldwell H, Dixon MJ, Meehan RR, Harrison DJ: Targeting of Rac GTPases blocks the spread of intact human breast cancer. Oncotarget 3:608-619, 2012
  PubMed Abstract
• Hackett JA, Reddington JP, Nestor CE, Dunican DS, Branco MR, Reichmann J, Reik W, Surani MA, Adams IR, Meehan RR: Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline
  Development 139:3623-3632, 2012.
  PubMed Abstract
• Nestor CE, Ottaviano R, Reddington J, Sproul D, Reinhardt D, Dunican D, Katz E, Dixon JM, Harrison DJ, Meehan RR: Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 22:467-477, 2012.
  PubMed Abstract
• Drake AJ, Liu L, Kerrigan D, Meehan RR, Seckl JR: Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects
  Epigenetics 6: 2011.PudMed Abstract
• Loughery JE, Dunne PD, O'Neill KM, Meehan RR, McDaid JR, Walsh CP: DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response.
  Hum Mol Genet 20(16):3241-3255, 2011. Pubmed Abstract
• Katz E, Dubois-Marshall S, Sims AH, Gautier P, Caldwell H, Meehan RR, Harrison DJ: An In Vitro Model That Recapitulates the Epithelial to Mesenchymal Transition (EMT) in Human Breast Cancer. PLoS One 6(2):e17083, 2011. PubMed Abstract
• Nestor, C.; Ruzov, A.; Meehan, R.R. and Dunican, D.S. Enzymatic approaches and bisulfite sequencing cannot distinguish between 5-methylcytosine and 5-hydroxymethlcytosine in DNA. BioTechniques 48(4):317-319, 2010
• Pennings, S. and Meehan, R. R. Chromatin Remodeling and Cancer. In: Cancer Epigenetics. Tollefsbol, T.(ed.), CRC Press, 253-264, 2009
• Ruzov, A.; Hackett, J.A.; Prokhortchouk, A.; Reddington, J.P.; Madej, M.J.; Dunican, D.S.; Prokhortchouk, E.; Pennings, S. and Meehan, R.R. The interaction of xKaiso with xTcf3: a revised model for integration of epigenetic and Wnt signalling pathways.
  Development 136:723-727, 2009 PubMed Abstract
• Ruzov, A.; Savitskaya, E.; Hackett, J.A.; Reddington, J.P.; Prokhortchouk, A.; Madej, M.J.; Chekanov, N.; Li, M.; Dunican, D.S.; Prokhortchouk, E.; Pennings, S. and Meehan, R.R. The non-methylated DNA-binding function of Kaiso is not required in early Xenopus laevis development. Development 136:729-738, 2009 PubMed Abstract
• Ruzov, A.; Shorning, B.; Mortusewicz, O.; Dunican, D.S.; Leonhardt, H. and Meehan, R.R. MBD4 and MLH1 are required for apoptotic induction in xDNMT1-depleted embryos.
  Development 136(13):2277-2286, 2009 PubMed Abstract
• Dunican, D.S.; Ruzov, A.; Hackett, J.A. and Meehan, R.R. xDnmt1 regulates transcriptional silencing in pre-MBT Xenopus embryos independently of its catalytic function.
  Development 135(7):1295-1302, 2008 PubMed Abstract
• Taylor, J.; Moore, H.; Beaujean, N.; Gardner, J.; Wilmut, I.; Meehan, R. and Young, L. Cloning and expression of sheep DNA methyltransferase 1 and its development-specific isoform.
  Mol Reprod Devel 76:501-513, 2009 PubMed Abstract