research

cancer & disease epigenetics

summary

Epigenetic modifications, including DNA methylation, encompass a range of regulatory factors that regulate the activity of underlying DNA. This includes controlling all gene expression, with differences in overall epigenetic profile accounting for the wide range of different cell and tissue types in our bodies, each of which contain essentially the same DNA sequence.

Epigenetic markings are sensitive to environmental influences such as dietary intake and lifestyle factors, especially during critical periods of early development. Disruption of epigenetic profile is a feature of all human cancers and is implicated in the risk of many common diseases. Our laboratory studies how the early environment interacts with epigenetic profile to regulate development and disease, particularly during pregnancy and early childhood.

group leader(s)

RSaffery

  Dr Richard Saffery
  Cancer & Disease Epigenetics
  Murdoch Childrens Research Institute
  Royal Children's Hospital
  Flemington Road
  Parkville Victoria 3052

  T +61 3 8341 6341
  E richard.saffery@mcri.edu.au

  group leader biography

current research projects

Project 1: Leukaemia epigenetics

Leukaemias are the most common forms of cancer in children. Despite this, the primary causes of disease are largely unknown. We have a comprehensive paediatric leukaemia research program focussed on understanding the relationship between genomic aberrations underpinning leukaemias, disruptions in epigenetic profile (DNA methylation and non-coding RNAs) and treatment responsiveness and long term outcome. We have one of the largest collections of archival leukaemia patient-derived bone marrows in existence internationally in addition to our ongoing prospective collection. With our close relationship with the RCH Children's Cancer Centre, we have rich clinical annotations associated with these specimens to facilitate the identification of robust clinically-relevant biomarkers associated with leukaemia outcome in children.


Project 2: Solid tumour epigenetics

Using strategies developed in our leukaemia research program, we are now studying the molecular disruptions associated with childhood solid tumours (primarily CNS in origin), that account for a disproportionally large number of childhood deaths amongst cancer sufferers. The key to improving outcomes lies in developing the appropriate tools for stratification of disease, understanding the pathways associated with each prognostic subgroup, and developing novel therapies targeting these pathways to facilitate a 'personalized' approach to treatment. We have assembled a team with expertise in paediatric tumour biology, anatomical pathology, genetics and epigenetics, as well as expertise in bioinformatics and data management to increase our understanding of the molecular mechanisms contributing to intractable solid tumours in children. In addition, we are examining the utility of tumour-derived cell lines as preclinical models for testing novel treatment protocols.

Project 3: Developmental epigenetics


The most powerful approach to understanding the interplay between genes, environment and epigenetics is through the establishment of prospective longitudinal birth cohort studies with detailed environmental, clinical and other data, with collection of multiple biospecimens.  In conjunction with the MCRI Early Life Epigenetics laboratory, we have established perinatal twin (PETS) and prematurity (PIES) cohorts and we are also leading the epigenetic analysis of the NHMRC-funded Barwon Infant Study (BIS). Recently, our team have begun coordinating the Epigenetics Work Package for a large EU-based multinational EarlyNutrition study with access to over 470,000 mothers and babies (EC-funded 2011-15).  The aim of each of these cohort-based studies is to examine how maternal environmental and lifestyle factors, and early postnatal environmental exposures, modify the developing childhood epigenome to modulate later risk of metabolic and other complex diseases in children.

Project 4: Complex disease epigenetics

The rapidly rising incidence of allergic and other immune-related diseases in early life is one of the clearest indicators that the developing immune system is vulnerable to modern environmental changes. Similar hypotheses are also being examined in relation to metabolic disorders such as obesity and TII diabetes. A range of environmental exposures are known to have effects on early life immune and metabolic function, potentially mediated epigenetically through a variety of processes that collectively modify gene expression and disease susceptibility. Our laboratory is working closely with clinical and epidemiological research partners to explore the link between specific environmental exposures and epigenetic disruption with childhood allergy, juvenile idiopathic arthritis, obesity and T2Diabetes. The overarching goal is to identify modifiable environmental risk factors and associated epigenetic biomarkers predictive of disease risk and/or outcome.

Project 5: Placental epigenetics

The human placenta facilitates the interaction between the mother and the developing fetus throughout pregnancy. In addition to its role in mediating the exchange of nutrients, vitamins and waste products between maternal and fetal circulations it is has important endocrine and immune functions. Aberrant placentation is associated with several adverse pregnancy outcomes including miscarriage, preeclampsia, fetal growth restriction and low birth weight. We study the effects of specific maternal environments on placental epigenetic profile and pregnancy outcome. Current projects include examining the effects of Vitamin D, folate, and alcohol on placental DNA methylation at the genome-wide levels and investigating the function of placenta-specific tumour suppressor gene methylation. We are currently banking excess first trimester Chorionic Villous Sampling (CVS) tissue and maternal serum screening samples as part of a study for later identification of epigenetic biomarkers predictive of adverse pregnancy outcomes.

team members

  • Zac Chatterton - PhD Student (UoM Paeds)
  • Anna Czajko - Technical Officer
  • Esteban Gimenez - Occupational Trainee
  • Douglas Hacking - Honorary Research Fellow
  • Alexandra Ivan - OBSERVER
  • Eric Joo - Research Assistant
  • Doris Lin - PhD Student (UoM Paeds)
  • David Martino - Research Officer
  • Leah Morenos - PhD Student (UoM Paeds)
  • Jane Ng - Research Assistant
  • Boris Novakovic - PhD Student (UoM Paeds)
  • Joanne Ryan - Postdoctoral Research Officer
  • Alex Sexton-Oates - Honours Student (UoM Paeds)
  • Nick Wong - Senior Research Officer

publications

  • Abad C., Antczak DF., Carvalho J., Chamley LW., Chen Q., Daher S., Damiano AE., Dantzer V., Diaz P., Dunk CE., Daly E., Escudero C., Falcon B., Guillomot M., Han YW., Harris LK., Huidobro-Toro JP., Illsley N., Jammes H., Jansson T., Johnson GA., Kfoury JR., Marin R., Murthi P., Novakovic B., Myatt L., Petroff MG., Pereira FTV., Pfarrer C., Redman CWG., Rice G., Saffery R., Tolosa JM., Vaillancourt C., Wareing M., Yuen R., Lash GE. IFPA Meeting 2010 Workshop Report I: Immunology; Ion transport; Epigenetics; Vascular reactivity; Epitheliochorial placentation; Proteomics. PLACENTA 32 (2011) PubMed
  • Al-Khan A., Aye IL., Barsoum I., Borbelyd A., Cebral E., Cerchi G., Clifton VL., Collins S., Cotechini T., Davey A., Flores-Martin J., Fournier T., Franchi AM., Fretes RE., Graham CH., Godbole G., Hansson SR., Headley PL., Ibarra C., Jawerbaum A., Kemmerling U., Kudo Y., Lala PK., Lassance L., Lewis RM., Menkhorst E., Morris C., Nobuzane T., Ramos G., Rote N., Saffery R., Salafia C., Sarr D., Schneider H., Sibley C., Singh AT., Sivasubramaniyam TS., Soares MJ., Vaughan O., Zamudio S., Lash GE. IFPA Meeting 2010 Workshops Report II: Placental pathology; Trophoblast invasion; Fetal sex; Parasites and the placenta; Decidua and embryonic or fetal loss; Trophoblast differentiation and syncytialisation. PLACENTA 32 (2011) PubMed
  • Cobb JE., Wong NC., Yip LW., Martinick J., Bosnich R., Sinclair RD., Craig JM., Saffery R., Harrap SB., Ellis JA. Evidence of increased DNA methylation of the androgen receptor gene in occipital hair follicles from men with androgenetic alopecia. BRITISH JOURNAL OF DERMATOLOGY 165 (1) : 210 - 213(2011) PubMed
  • Drini M., Wong NC., Scott HS., Craig JM., Dobrovic A., Hewitt CA., Dow C., Young JP., Jenkins MA., Saffery R., Macrae FA. Investigating the Potential Role of Genetic and Epigenetic Variation of DNA Methyltransferase Genes in Hyperplastic Polyposis Syndrome. PLOS ONE 6 (2) (2011) PubMed
  • Evans-Galea MV., Carrodus N., Rowley SM., Corben LA., Tai G., Saffery R., Galati JC., Wong NC., Craig JM., Lynch DR., Regner S., Brocht AFD., Perlman SL., Bushara K., Gomez CM., Wilmot GR., Li L., Varley E., Delatycki MB., Sarsero JP. FXN methylation predicts expression and clinical outcome in friedreich ataxia. ANNALS OF NEUROLOGY (2011)
  • Gordon L., Joo JHE., Andronikos R., Ollikainen M., Wallace EM., Umstad MP., Permezel M., Oshlack A., Morley R., Carlin JB., Saffery R., Smyth GK., Craig JM. Expression discordance of monozygotic twins at birth Effect of intrauterine environment and a possible mechanism for fetal programming. EPIGENETICS 6 (5) : 579 - 592(2011) PubMed
  • Hogan LE., Meyer JA., Yang J., Wang JH., Wong N., Yang WJ., Condos G., Hunger SP., Raetz E., Saffery R., Relling MV., Bhojwani D., Morrison DJ., Carroll WL. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. BLOOD 118 (19) : 5218 - 5226(2011) PubMed
  • Martino DJ., Tulic M., Gordon L., Hodder M., Richman T., Metcalfe J., Prescott SL., Saffery R. Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans. EPIGENETICS 6 (9) : 1085 - 1094(2011) PubMed
  • Novakovic B., Gordon L., Wong NC., Moffett A., Manuelpillai U., Craig JM., Sharkey A., Saffery R. Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function. MOLECULAR HUMAN REPRODUCTION 17 (6) : 344 - 353(2011) PubMed
  • Novakovic B., Yuen RK., Gordon L., Penaherrera MS., Sharkey A., Moffett A., Craig JM., Robinson WP., Saffery R. Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors. BMC GENOMICS 12 (529) (2011) PubMed
  • Olsson CA., Moyzis RK., Williamson E., Ellis JE., Parkinson-Bates M., Patton GC., Dwyer T., Romaniuk H., Moore EE. Gene-environment interaction in problematic substance use : interaction between DrD4 and insecure attachments. Addiction Biology (2011)
  • Prescott S., Saffery R. The role of epigenetic dysregulation in the epidemic of allergic disease. Clinical Epigenetics (2011)
  • Prescott SL., Tulic M., Osei-Kumah A., Richman T., Crook M., Martino D., Dunstan JA., Novakovic B., Saffery R., Clifton VL. Reduced placental FOXP3 associated with subsequent infant allergic disease. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 128 (4) : 886 - 887(2011) PubMed
  • Ryan J., Ludbrook L., Wilhelm D., Sinclair A., Koopman P., Bernard P., Harley VR. Analysis of Gene Function in Cultured Embryonic Mouse Gonads Using Nucleofection. SEXUAL DEVELOPMENT 5 (1) : 7 - 15(2011) PubMed
  • Saffery R., Morley R., Carlin JB., Joo EJ., Ollikainen M., Novakovic B., Andronikos R., Li X., Loke YJ., Carson N., Wallace EM., Umstad MP., Permezel M., Galati JC., Craig JM. The Peri/post-natal Epigenetic Twins Study. International Journal of Epidemiology (2011)
  • Tan TH., Ellis JA., Saffery R., Allen KJ. The role of genetics and environment in the rise of childhood food allergy. CLINICAL AND EXPERIMENTAL ALLERGY (2011) PubMed
  • Wu XR., Bandopadhayay P., Ng J., Ashley D., Chow CW. The evolution of the histology in pleomorphic xanthoastrocytomas in children: a study of 15 cases. PATHOLOGY 43 (1) : 9 - 16(2011) PubMed

competitive funding

National Health and Medical Research Council
European Commission (FP7)
Australian Research Council
Perpetual Trustees
Brockhoff Foundation
Ramaciotti Foundation
Scobie & Claire McKinnon Foundation

collaborations & affiliations

Early Nutrition research consortium (EU-based)
International Childhood Cancer Cohort Consortium
Australian Epigenetics Alliance
Victorian Epigenetics Group
Australian Childrens Cancer Research Alliance
Victorian Cancer Biobank (from 2012)