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Wolf Reik and Jennifer Nichols Project

Professor Wolf Reik and Professor Jennifer Nichols

Epigenetic regulation of cell fate decisions in mammalian development

The mammalian embryo makes fundamentally important cell fate decisions during gastrulation which set up the primary germ layers (endoderm, mesoderm, ectoderm) with subsequent development of all major organ systems. While signaling systems, mechanical forces, transcription factors, and epigenetic regulation are all implicated in cell fate decisions, how these systems integrate information to control cell fate is not known. You will use state of the art single cell multi-omics methods to interrogate individual cells as they make decisions to become particular cell types during gastrulation. You will use CRISPR/Cas9 genome and epigenome editing to manipulate epigenetic regulators and marks to understand their impact on cell fate.

We have begun to systematically characterize all cells in gastrulating mouse embryos by single cell sequencing. We have found that coherent cell fate transitions (establishing cell identity through characteristic transcriptional networks) are often preceded by heightened transcriptional heterogeneity or noise. Furthermore, large scale epigenetic remodeling (such as for example de novo methylation of the genome) also occurs prior to overt cell differentiation, and may influence transcriptional heterogeneity and differentiation programmes. Indeed mouse mutants in DNA methylation and other epigenetic modifiers have gastrulation defects, attesting to the importance of these systems for initiating or sustaining cell identity switches.

In order to understand the integration of epigenetic regulation and transcription during differentiation we have developed single cell sequencing methods which interrogate the transcriptome, methylome, and chromatin accessibility all in the same single cell. Novel computational and statistical algorithms connect transcriptional with epigenome variability, for example at the level of enhancer or promoter methylation and nucleosome accessibility. An important question is which epigenetic marks could be instructive for differentiation and which epigenetic marks lock differentiation states in instead. You will systematically catalogue this combined single cell information for hundreds to thousands of cells, building up an exciting and informative map of epigenetic and transcriptional transitions during gastrulation.

Relevant references

Eckersley-Maslin et al 2019 Genes Dev, Pijuan-Sala et al 2019 Nature, Argelaguet et al 2019 Nature

http://www.babraham.ac.uk/our-research/epigenetics/wolf-reik; http://www.sanger.ac.uk/people/directory/reik-wolf