Award details

To study epigenetic mechanisms that create heterogeneity and functional diversity in stem cells, development and between individuals

Reference	BBS/E/B/000C0422
Principal Investigator / Supervisor	Dr Gavin Kelsey
Co-Investigators / Co-Supervisors	Dr Maria Casanueva, Dr Myriam Hemberger, Dr Jonathan Houseley, Dr Peter Rugg-Gunn, Dr Philipp Voigt
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	2,395,341
Status	Current
Type	Institute Project
Start date	01/04/2017
End date	31/03/2023
Duration	59 months

Abstract

Single-cell technologies have revealed extensive heterogeneity between and within tissues, enabling important new questions in development and ageing to be experimentally addressed. During the course of the last ISPG, for example, we developed scBS-seq23 and the first combined method to sequence the transcriptome and epigenome (methylome) from the same single cell (scM&T-seq24). These new approaches have identified an exciting mechanism by which the creation of epigenetic heterogeneity can be connected with the generation of transcriptional heterogeneity. Building on this work, the new ISPG objective will investigate and model how epigenetic heterogeneity is established and, in turn, leads to diversification of cell phenotype and function during development and ageing. We will test the prediction that as cells transition towards a pluripotent state that is primed for lineage commitment, they acquire epigenetic marks including H3K27me3 and DNA methylation at regulatory regions that act to constrain the expression of developmental TFs25. Rapid turnover of these marks is expected to generate epigenetic heterogeneity between cells and thereby create transcriptional heterogeneity. We propose that this mechanism enables primed pluripotent cells to remain uncommitted, yet able to explore transiently different states that predispose cells toward different lineage choices upon receipt of differentiation stimuli. This informs an important new concept for understanding and controlling lineage commitment during stem cell differentiation and embryo development. In complementary work, using the model organism C. elegans, we have established that there is widespread heterogeneity in a subset of genes that are rate-limiting for ageing. We will, therefore, investigate how epigenetic and transcriptional heterogeneity is established between genetically identical organisms, and how such heterogeneity contributes to variability in key traits during ageing such as lifespan. This Objective uses mouse and human stem cells and C. elegans to explore the emergence and consequences of epigenetic heterogeneity.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Stem Cells
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

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search