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.
Sandovici I, Georgopoulou A, Perez-Garcia V, Hufnagel A, Lopez-Tello J, Lam BYH, Schiefer SN, Gaudreau C, Santos F, Hoelle K, Yeo GSH, Burling K, Reiterer M, Fowden AL, Burton GJ, Branco CM, Sferruzzi-Perri AN, Constância M (2022) The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth. Dev Cell doi: 10.1016/j.devcel.2021.12.005. Online ahead of print. PMID: 34963058
Angiolini E, Sandovici I, Coan PM, Burton GJ, Sibley CP, Fowden AL, Constância M (2021) Deletion of the imprinted Phlda2 gene increases placental passive permeability in the mouse. Genes 12:639 doi: 10.3390/genes12050639. PMID: 33922969. PMCID: PMC8146920
Sandovici I, Hammerle CM, Virtue S, Vivas-Garcia Y, Izquierdo-Lahuerta A, Ozanne SE, Vidal-Puig A, Medina-Gomez G, Constância M (2021) Autocrine IGF2 programmes beta-cell plasticity under conditions of increased metabolic demand. Sci Rep 11:7717 doi: 10.1038/s41598-021-87292-x. PMID: 33833312. PMCID: PMC8032793
Andrade S, Morais T, Sandovici I, Seabra AL, Constância M, Monteiro MP (2021) Adipose tissue epigenetic profile in obesity-related dysglycemia – a systematic review. Front Endocrinol (Lausanne) 12:681649. doi: 10.3389/fendo.2021.681649. PMID: 34290669. PMCID: PMC8288106
Hammerle CM, Sandovici I, Brierley GV, Smith NM, Zimmer WE, Zvetkova I, Prosser HM, Sekita Y, Lam BYH, Ma M, Cooper WN, Vidal-Puig A, Ozanne SE, Medina-Gomez G, Constância M (2020) Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function. PLoS Genet 16(10):e1009069. doi: 10.1371/journal.pgen.1009069. PMID: 33057429. PMCID: PMC7678979
Lopez-Tello J, Perez-Garcia V, Khaira J, Kusinski LC, Cooper WN, Andreani A, Grant I, Fernandez de Liger E, Liam BY, Hemberger M, Sandovici I, Constância M, Sferruzzi-Perri AN (2019) Fetal and trophoblast PI3K p110 alpha have distinct roles in regulating resource supply to the growing fetus in mice. Elife 8:e45282. doi: 10.7554/eLife.45282. PMID: 31241463. PMCID: PMC6634971
Gong S, Johnson MD, Dopierala J, Gaccioli F, Sovio U, Constância M, Smith GC, Charnock-Jones DS (2018) Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in human placenta. Epigenetics 13:228-239. doi: 10.1080/15592294.2018.1429857. PMID: 29376485. PMCID: PMC5989156
Pestana D, Teixeira D, Meireles M, Marques C, Norberto S, Sa C, Fernandes VC, Correia-Sa L, Faria A, Guardao L, Guimaraes JT, Cooper WN, Sandovici I, Domingues VF, Delerue-Matos C, Monteiro R, Constancia M, Calhau C (2017) Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p’-DDE. Sci Rep 7:2738. doi: 10.1038/s41598-017-02885-9. PMID: 28572628. PMCID: PMC5453948
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.