(Epi)genetics of Growth and Metabolism
We are interested in the study of genetic and epigenetic mechanisms that control fetal and postnatal growth, and the metabolic basis of growth. Epigenetics is a new and exciting field in biomedical research that refers to the heritable marking of genes by chemical tags, which orchestrate, together with transcription factors, a myriad of genomic functions. We use a combination of cellular and whole organism-based systems to address a number of key questions:
- How does metabolic flux affect cell growth and how do cells coordinate their growth with nutrient availability?
- How is organ size and body size coordinated?
- How do the fetus and the mother communicate with the placenta to ensure a normal growth trajectory?
- What are the developmental consequences of defective metabolic growth signaling?
- What is the molecular basis by which nutrition and the environment elicit (epi)genomic responses that in turn lead to physiological adaptations?
Current projects in the lab are focused on imprinted genes as epigenetic regulators of fetal demand and supply of maternal nutrients, System A amino-acid transporters in the metabolic regulation of growth, microRNAs involved in organ and body size determination and epigenetic regulation of long-range promoter-enhancer interactions that determine programming of obesity and diabetes in later life.
Our work has important clinical implications, as we aim to understand the basic principles that govern genetic and epigenetic regulation of growth. For example, fetal growth impairment affects high numbers of human pregnancies and is associated with a variety of pregnancy complications, such as pre-eclampsia and gestational diabetes, and is a well-known risk factor for neonatal death, cerebral palsy and diseases in later life (behavioural, cardiovascular and metabolic dysfunction).
Mikaelsson MA, Constancia M, Dent CL, Wilkinson LS & Humby : T (2013). Placental programming of anxiety in adulthood revealed by Igf2-null models. Nat Commun 4:2311
Sandovici I, Hammerle CM, Ozanne SE & Constancia M (2013). Developmental and environmental epigenetic programming of the endocrine pancreas: consequences for type 2 diabetes. Cell Mol Life Sci 70:1575-95
Sandovici I, Hoelle K, Angiolini E & Constancia M (2012) Placental adaptations to the maternal-fetal environment: implications for fetal growth and developmental programming. Reprod Biomed Online 25:68-69
Haley VL, Barnes DJ, Sandovici I, Constancia M, Graham CF, Pezzella F, Buhnemann C, Carter EJ & Hassan AB (2012). Igf2 pathway dependency of the Trp53 developmental and tumor phenotypes. EMBO Mol Med 4: 705-718
Khulan B, Cooper WN, Skinner B, Bauer J, Owens S, Prentice AM, Belteki G, Constancia M, Dunger D & Affara NA (2012). Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia. Hum Mol Genet221:2086-2101
Cooper WN, Khulan B, Owens S, Elks CE, Seidel V, Prentice AM, Belteki G, Ong KK, Affara NA, Constancia 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 26:1782-1790
Ozanne S, Sandovici I & Constancia M (2011). Maternal diet, aging and diabetes meet at a chromatin loop. Aging 3:548-554
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, Constancia 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 108:5449-5454
Sferruzzi-Perri AN, Vaughan OR, Coan PM, Suciu MC, Darbyshire R, Constancia M, Burton GJ & Fowden AL (2011). Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. Endcorinology 152:3201-3212
Angiolini E, Coan P, Sandovici I, Iwajomo OH, Peck G, Burton GJ, Sibley CP, Reik W, Fowden AL & Constancia M (2011). Deveopmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2-mediated overgrowth. FASEB J 25:1737-1745
Peltry CJ, Evans ML, Wingate DL, Ong KK, Reik W, Constancia M &Dunger BD (2010). Raised late pregnancy glucose concentrations in mice carryign pups with targeted disruption of H19 delta 13. Diabetes 59:282-286
Dilworth M, Kusinski L, Cowley E, Ward S, Husain S, Constancia M, Sibley C & Galzier J (2010). Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport. Proc Natl Acad Sci USA 107:3894-3899
Ozanne S & Constancia M (2007). Mechanisms of Disease: The developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endo & Met 3:539-546
Constancia M, Angiolini E, Sandovici I, Smith P, Smith R, Kelsey G, Dean W, Ferguson-Smith A, Sibley CP, Reik W & Fowden A (2005). Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems. Proc Natl Acad Sci USA 102:19219-19224
Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL & Constancia M (2004). Placental-specific insulin-like groeth factor (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci USA 101:8202-8208
Constancia M, Kelsey G & Reik W (2004). Resourceful Imprinting. Nature 432:53-57
Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C & Reik W (2002). Placental Igf2 is a major modulator of fetal growth. Nature 417:945-948
Constancia M, Dean W, Lopes S, Moore T, Kelsey G & Reik W (2000). Deletion of a silencer element i Igf2 results in loss of imprinting independent of H19. Nature Genet 26:203-206