DR RICHARD MEEHAN
Chromosomes and Gene Expression
|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|
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/.
- Sproul D and Meehan RR. Genomic insights into cancer-associated aberrant CpG island hypermethylation. Brief. Funct. Genomics. 2013
- Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, and Meehan RR Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol. 13: R84. 2012
- Reichmann J, Reddington JP, Best D, Read D, Ollinger R, Meehan RR, and Adams IR. 2013. The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. Hum. Mol. Genet. 2013
- Reddington JP, Pennings S, and Meehan RR. Non-canonical functions of the DNA methylome in gene regulation. Biochem. J. 451: 13-23. 2013
- Thomson JP, Lempiainen H, Hackett JA, Nestor CE, Muller A, Bolognani F, Oakeley EJ, Schubeler D, Terranova R, Reinhardt D, Moggs JG, and Meehan RR. Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol. 13: R93. 2012
- Lempiainen H, Couttet P, Bolognani F, Muller A, Dubost V, Luisier R, Espinola AR, Vitry V, Unterberger EB, Thomson JP, Treindl F, Metzger U, Wrzodek C, Hahne F, Zollinger T, Brasa S, Kalteis M, Marcellin M, Giudicelli F, Braeuning A, Morawiec L, Zamurovic N, Langle U, Scheer N, Schubeler D, Goodman J, Chibout SD, Marlowe J, Theil D, Heard DJ, Grenet O, Zell A, Templin MF, Meehan RR, Wolf RC, Elcombe CR, Schwarz M, Moulin P, Terranova R, and Moggs JG. 2013. Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion. Toxicol. Sci. 131: 375-386. 2013
- 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
- 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
- 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.
- 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.
- 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