Epigenetics is an exciting and rapidly moving field that impacts basic biomedical research and clinical medicine. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs provide dynamic, heritable and reversible ways of modulating genome function. They affect a number of processes such as chromosome architecture, chromatin function and gene expression.
We are interested in understanding how epigenetic mechanisms regulate gene activity and how they respond to environmental cues (e.g. nutrition), with a focus on imprinted genes and developmental pathways that link growth with metabolic function.
The work in the lab is divided into two related areas:
1- Genomic imprinting and fetal growth
Genomic imprinting is a form of epigenetic regulation in mammals which results in the silencing of one of the two gene copies, according to parental origin. Imprinted genes have key roles in maternal allocation of resources that affect the development of the placenta, fetal and infant growth, glucose and fat metabolism as well as adult behaviours. We are studying how imprinted genes control fetal growth and placental function and their roles in metabolic functions using genetically engineered mouse models, in vivo physiological assays, and cell based systems.
2- Epigenetics and gene-environment interactions
Epigenetics may underpin interactions between the genome and the environment. Environmentally-induced changes to the epigenome that may occur during the “waves” of genome-wide epigenetic reprogramming in early development are likely to have long term health consequences. We aim at finding key genes that, when epigenetically de-regulated by sub-optimal nutrition in early development, may contribute to onset and risk of diabetes and obesity phenotypes in later life. We use a combination of (epi)genomic-wide screens and in vitro manipulation of epigenetic machinery, in rodent and human biological materials, to detect loss of epigenetic cellular memory.
Sferruzzi-Perri AN, Lopez-Tello J, Fowden AL & Constância M (2016). Maternal and fetal genomes interplay through phosphoinositol 3-kinase (PI3K)-p110alpha signalling to modify placental resource allocation. Proc Natl. Acad Sci USA, 113:11255-11260. PMID: 27621448. PMCID:PMC5056071.
Sandovici I, Hammerle CM, Cooper WN, Smith NH, Tarry-Adkins JL, Dunmore BJ, Bauer J, Andrews SR, Yeo GS, Ozanne SE & Constância M (2016). Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets. Diabetologia, 59:502-11. PMID:26699651. PMCID:PMC4742511.
Ferron SR, Radford EJ, Domingo-Muelas A, Kleine I, Ramme A, Gray D, Sandovici I, Constância M, Ward A, Menheniott TR & Ferguson-Smith AC (2015). Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis. Nat Commun 6:8265. PMID: 26369386. PMCID:PMC4579569.
Quilter CR, Cooper WN, Cliffe KM, Skinner BM, Prentice PM, Nelson L, Bauer J, Ong KK, Constância M, Lowe WL, Affara NA & Dunger DB (2014). Impact on offspring methylation patterns of maternal gestational diabetes mellitus and intrauterine growth restraint suggest common genes and pathways linked to subsequent type 2 diabetes risk. FASEB J 28:4868-79. PMID: 25145626.
Mikaelsson MK, Constância M, Dent C, Wilkinson LS & Humby T. (2013). Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun, 4:2311. PMID: 23921428.
Sferruzzi-Perri AN, Vaughan OR, Haro M, Cooper WN, Musial B, Charalambous M, Pestana D, Ayyar S, Ferguson-Smith AC, Burton GJ, Constância M & Fowden AL (2013). An obesogenic diet during mouse pregnancy modifies maternal nutrient portioning and the fetal growth trajectory. FASEB J, 27:3928-37. PMID: 23825226.
Sandovici I, Hammerle CM, Ozanne SE & Constância M (2013). Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes. Cell Mol Life Sci, 70:1575-95. PMID: 23463236.
Sandovici I, Hoelle K, Angiolini E & Constância M. (2012). Placental adaptations to the maternal-fetal environment: implications for fetal growth and developmental programming. Reprod Biomed Online, 25:68-89. PMID: 22560117.
Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constância M, & Dunger DB. (2012). DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J, 26:1782-90. PMID: 22267336.
Sandovici I*, Smith NH*, Dekker-Nitert M, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns WJ, Tadayyon M, O’Neill LP, Murrell A, Ling C, Constância M* & Ozanne S*. (2011). Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at Hnf4a gene in rat pancreatic islets. Proc Natl. Acad Sci USA, 108:5449-54. PMID: 21385945. PMCID: PMC3069181.
Sferruzzi-Perri AN, Vaughan OR, Coan PM, Suciu MC, Darbyshire R, Constância M, Burton GJ & Fowden AL. (2011). Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. Endocrinology, 152:3202-12. PMID: 21673101.
Angiolini E, Coan P, Sandovici I, Iwajomo OH, Peck G, Burton GJ, Sibley CP, Reik W, Fowden AL & Constância M. (2011). Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2-mediated overgrowth. FASEB J, 25:1737-45. PMID: 21282203.
Petry CJ, Evans ML, Wingate DL, Ong KK, Reik, W, Constância M & Dunger BD. (2010). Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19 delta 13. Diabetes, 59:282-6. PMID: 19794064. PMCID: PMC2797934.
Dilworth M, Kusinski L, Cowley E, Ward S, Husain S, Constância M, Sibley C & Glazier J (2010). Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport. Proc Natl, Proc Natl Acad Sci USA, 107:3894-9. PMID: 20133672. PMCID: PMC2840526.