Dr Marika Charalambous Group
Full Name: Marika Charalambous
Position: Reader in Developmental Epigenetics
Research (themes): Developmental regulation of metabolic axes by imprinted genes. Endocrine communication between mother and offspring during pregnancy.
Background (brief bio):
I joined the department of Medical and Molecular Genetics in October 2017.
My research career has focused primarily on the relationship between epigenetic gene dosage control and developmental physiology. Much of my work has utilised imprinted genes in the mouse as experimental models, since the epigenetic modulation of these exquisitely dosage-sensitive genes has important consequences for prenatal growth and development in mouse and man. During my postdoctoral work I investigated the actions of imprinted genes on mouse chromosome 12 in the development of brown adipose tissue (Ferguson-Smith lab, University of Cambridge); described a mouse model with defects in placental development and growth as a result of the loss of function of the imprinted Grb10 gene (Ward lab, University of Bath). In addition I undertook a training postdoctoral position in metabolic medicine in order to link my interest in prenatal growth and development with lifelong outcomes on metabolic health (Withers Lab, Imperial College London). I was appointed to an Early Careers Fellowship at the Centre for Endocrinology at Queen Mary University of London in early 2013, and became a Senior Lecturer in 2015.
Summary of Research
Imprinting, growth and maternal-foetal interactions
In the 1980s mouse nuclear transplantation experiments revealed that both parental genomes are required for successful development to term. This non-equivalence of parental genomes is due to imprinted genes expressed predominantly from only one parental chromosome. More than 70 imprinted genes have now been discovered and the functions of many assessed in a range of murine models. Many of the same genes are also imprinted in humans, and uniparental inheritance of these genomic regions causes paediatric growth disorders such as Beckwith-Wiedemann or Prader-Willi syndromes. The first genes shown to be imprinted were the foetal growth factor Igf2 (Figure 1) and its inhibitor Igf2r. Since then it has emerged that the majority of imprinted genes modulate fetal growth and resource acquisition in a variety of ways. First, imprinted genes are required for the development of a functional placenta, the organ that mediates the exchange of nutrients between mother and fetus. Second, these genes act in an embryo-autonomous manner to affect the growth rate and organogenesis. Finally, imprinted genes can signal the nutritional status between mother and fetus, and can modulate levels of maternal care. Importantly, many imprinted genes have recently been shown to affect postnatal growth and metabolism. As intrauterine growth retardation is often associated with increased risk of metabolic syndrome and cardiovascular disease, it is crucial to understand how the modulation of this dosage-sensitive, epigenetically regulated class of genes can contribute to growth, disease, and lifelong health.
Figure 1. Expression of Igf2 in the midgestation mouse embryo and placenta. Gene expression is labelled in purple.
Our work is focused on the following questions:
1) How do imprinted genes modulate the transfer of nutrients between mother and foetus during pregnancy?
a) Investigating imprinted gene function in the placenta.
We have utilised conditional targeting combined with fluorescent reporters (Figure 2) to understand the role of imprinted genes in the developing placenta, and how this relates to embryonic growth.
b) Imprinted gene products signal to the mother to alter her response to fasting during pregnancy.
We recently showed that the product of the paternally-expressed Delta-like 1 homologue gene (DLK1) is synthesised by fetal tissues during embryogenesis and enters the maternal circulation during pregnancy. High levels of DLK1 in the mother’s blood promotes ‘accelerated starvation of pregnancy’ – the rapid breakdown of adipose stores and utilisation of ketones for fuel by the mother in response to food restriction. This spares glucose for fetal growth. Embryos with a deletion of the Dlk1 gene are small. Moreover, we showed that maternal DLK1 levels are in low in women with complicated pregnancies who give birth to small babies
Figure 3. DLK1 produced by the fetus enters the maternal circulation and promotes rapid breakdown of adipose stores in response to food restriction.
2) Can modulations in imprinted gene dosage modulate body composition to alter metabolic set points for the lifetime of the individual?
We are using conditional targeting combined with fluorescent reporters (Figure 4) to understand the role of imprinted genes in the developing adipose tissue, and relating this to adipose turnover and glucose homeostasis over the lifetime of the individual.
Figure 4. GFP labelling of developing adipose tissue in the mouse. Developing brown adipose tissue is labelled green in the interscapular region of a late gestation embryo.