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Metabo-Devo of the placenta: Understanding the metabolic determinants of early placental development Supervisors: Dr Irving Aye, Professor Stephen Charnock-Jones

Metabo-Devo of the placenta: Understanding the metabolic determinants of early placental development

Supervisors: Dr Irving Aye, Professor Stephen Charnock-Jones

During early placental development, trophoblast cells face diverse metabolic challenges including nutrient and oxygen-limited microenvironments and changing environmental conditions. It is also during this stage that vast changes in gene expression coincide with reprogramming of cellular metabolism. However, it is unclear how trophoblast cells assess and respond to their metabolic resources to achieve a coordinated effect on cell proliferation, differentiation, and placental development. Cell metabolism is conventionally viewed as a means of obtaining bioenergy for cellular homeostasis or building blocks for biomass growth. However, metabolic intermediates can also strongly influence gene expression through additional non-bioenergetic functions, for instance as signalling mediators that control key transcription factors involved in developmental gene expression programs or as rate-limiting substrates in a variety of epigenetic processes.

This project aims to understand the mechanistic links between cell metabolism and transcriptional/epigenetic programs directing trophoblast cell proliferation and differentiation. Key questions to be addressed are: How does the placenta respond and adapt to changes in varying environmental conditions? How does cellular metabolism influence gene regulatory networks in placental development? The underlying hypothesis is that trophoblast metabolism directs gene expression programs regulating differentiation by controlling the availability of metabolic intermediates necessary for transcriptional and epigenetic processes. You will utilise primary trophoblast cells isolated from human term placentas as well as the recently derived human trophoblast stem cells and trophoblast organoids. Transcriptional and epigenetic changes associated with differentiation will be examined by RNA-seq and ChIP-seq combined with single-cell sequencing approaches to identify intermediate populations during differentiation. Phenotyping of cell metabolism will be performed using extracellular flux analysis, global and targeted metabolomic profiling and isotope labelled metabolic flux analysis. Metabolic enzymes will then be targeted using CRISPR/Cas9, siRNA transfection, and lentiviral transduction approaches to examine the metabolic dependency of trophoblast cells and their role in regulating gene expression networks during trophoblast differentiation.

This project will explore the unchartered field of “Placental Metabo-Devo”, i.e. the different mechanisms by which metabolism impacts on the processes governing placental development. Addressing these fundamental biological questions may help us understand novel mechanisms of placental-related pregnancy complications such as miscarriage, preeclampsia and fetal growth restriction.

For further information please contact Dr Irving Aye, ia319@medschl.cam.ac.uk