Miguel Constância
University Lecturer in Reproductive Biology
Department of Obstetrics and Gynaecology
Research Interests
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.
Our work is funded by the BBSRC, MRC, Royal Society and the EU Epigenome Network of Excellence.
Selected Publications
Dilworth MR, Kusinski LC, Cowley E, Ward BS, Husain SM, Constância M, Sibley CP, Glazier JD. (2010). Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport. Proc Natl Acad Sci USA, 107(8):3894-9. PMID: 20133672. PMCID: PMC2840526.
Coan PM, Vaughan OR, Sekita Y, Finn SL, Burton GJ, Constancia M, Fowden AL. (2010). Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice. J Physiol, 588(Pt 3):527-38. PMID: 19948659. PMCID: PMC2825615.
Petry CJ, Evans ML, Wingate DL, Ong KK, Reik W, Constância M, Dunger DB. (2010). Raised Late Pregnancy Glucose Concentrations in Mice carrying Pups with Targeted Disruption of H19{Delta}13. Diabetes, 59(1):282-6. PMID: 19794064. PMCID: PMC2797934.
Coan PM, Fowden AL, Constancia M, Ferguson Smith AC, Burton GJ, Sibley CP. (2008). Disproportional effects of Igf2 knockout on placental morphology and diffusional exchange characteristics in the mouse. J Physiol, 586(Pt 20):5023-32. PMID: 18755750. PMCID: PMC2614051.
Coan PM, Angiolini E, Sandovici I, Burton GJ, Constancia M, Fowden AL. (2008). Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice. J Physiol, 586(Pt 18):4567-76. PMID: 18653658. PMCID: PMC2614013.
Ozanne S & Constância M. (2007). Mechanisms of Disease: The developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endo & Met, 3(7):539-546. PMID: 17581623.
Monk D, Sanches R, Arnaud P, Apostolidou S, Hills FA, Abu-Amero S, Murrell A, Friess H, Reik W, Stanier P, Constância M & Moore GE. (2006). Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human. Human Mol Genet, 15:1259-69. PMID: 16531418.
Constância 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(52):19219-24. PMID: 16365304. PMCID: PMC1316882.
Constância M, Kelsey G & Reik W. (2004). Resourceful Imprinting. Nature, 432(7013):53-7. PMID: 15525980.
Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL & Constância M. (2004). Placental-specific Insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. Proc Natl Acad Sci USA, 101(21):8204-8. PMID: 15150410. PMCID: PMC419581
Lopes S, Lewis A, Hajkova P, Dean W, Oswald J, Forne T, Murrell A, Constância M, Bartolomei M, Walter J & Reik W. (2003). Epigenetic modification in the Igf2-H19 locus are controlled by a hierarchy of Dmrs and may involve long-range chromatin interactions. Hum Mol Genet, 12(3):295-305. PMID: 12554683.
Constância 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(6892):945-948. PMID: 12087403.
Murrell A, Heeson S, Bowden L, Constância M, Dean W, Kelsey G & Reik W. (2001). An intragenic methylated region in the imprinted Igf2 gene regulates transcription of the paternal allele. Embo Rep, 2(12):1101-1106. PMID: 11743023. PMCID: PMC1084166
Eden S, Constância M, Hashimshony T, Dean W, Goldstein B, Johnson A, Keshet I, Reik W & Cedar H. (2001). An upstream repressor element plays a role in Igf2 imprinting. EMBO J, 20(13):3518-3525. PMID: 11432838. PMCID: PMC125515.
Constância M, Dean W, Lopes S, Moore T, Kelsey G & Reik W. (2000). Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19. Nature Genet, 26(2):203-206. PMID: 11017078.