(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).
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
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
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.
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
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
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
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
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