Award details

To study epigenetic mechanisms regulating lineage commitment and cell potency

Reference	BBS/E/B/000C0421
Principal Investigator / Supervisor	Dr Gavin Kelsey
Co-Investigators / Co-Supervisors	Dr Maria Casanueva, Dr Myriam Hemberger, Dr Jonathan Houseley, Dr Teresa Rayon, Dr Peter Rugg-Gunn, Dr Stefan Schoenfelder, Dr Philipp Voigt
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	5,865,314
Status	Current
Type	Institute Project
Start date	01/04/2017
End date	31/03/2023
Duration	59 months

Abstract

This objective is a natural progression of our previous ISPG in which we have successfully established epigenomic profiles across a vast array of developmental stages during germ cell as well as pre- and post-implantation development, and of related stem cell types. We shall build on these advances and address key questions arising: notably, how are distinct, cell type-defining epigenetic patterns established at the mechanistic level to cement cell fate specification and, conversely, what are the critical chromatin features that enable the reversal to totipotency? Mathematical modelling integrating transcriptional, epigenetic and metabolic states will provide a quantitative mechanistic understanding of the control mechanisms underlying toti-/pluripotency, self-renewal and lineage differentiation pathways. Developmental progression is characterised by the transition of cellular plasticity from a totipotent zygote to the emergence of the first cell lineages at the blastocyst stage and ultimately the differentiation into highly specialised cell types. These steps are underpinned by the acquisition of epigenetic marks that help define, and lock in, cell fate. As such, totipotency is an ephemeral state intrinsic only to the fertilised zygote and 2-cell stage embryo, and describes the widest-possible plasticity of a cell to differentiate into all embryonic as well as extra-embryonic cell types. Despite its importance, little is known regarding the molecular mechanisms regulating this state, mostly due to limited and hard-to-obtain samples. However, the recent identification of a small subpopulation of embryonic stem cells (ESCs) that exhibits totipotent features (so-called 2C-like cells), together with transformative advances in single-cell technologies, has opened up this field to mechanistic investigations. Leading on from this, our work has shown that the timing of lineage commitment coincides perfectly with the onset of de novo DNA methylation, and results in the establishment of lineage-defining epigenomic patterns and hallmarks1-3. We have also explored how the epigenome integrates with the transcriptional landscape and how it is influenced by signalling pathways4,5. With this in-depth knowledge, a critical question is how the epigenetic machinery is targeted to different genomic sites to set up lineage-distinctive and cell potency-defining patterns. In parallel with experimental efforts, we will expand our modelling approaches of the first cell fate decision by integrating transcriptional, epigenetic as well as metabolic data to gain qualitative and quantitative insights into the regulators governing totipotency and cellular differentiation. Cellular metabolism is known to differ between the first cell lineages, in particular lipid metabolism, and metabolic state is recognised as an important modulator of cell plasticity that may thereby impact on the epigenome. Thus, integration of cell metabolic states into mathematical models, in parallel to our experimental efforts, will advance our understanding of how the epigenome is shaped to promote self-renewal and underpin the first cell fate decision events. This Objective involves close cross-ISP interactions with the Signalling ISP in relation to trophoblast stem cells (TSCs) and modelling of metabolic effects on epigenetic regulators on cell-fate decisions.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Stem Cells, Systems Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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