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Epigenetic regulation of cell fate decisions in mammalian development

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 switch 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/Cas 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.

 

We have already gained some preliminary insights into germ layer commitment from these studies. We find that neuroectoderm enhancers are already epigenetically primed (hypomethylated, chromatin accessible) in the early epiblast, but mesoderm and endoderm enhancers are not. They instead become acutely demethylated and accessible as cells ingress into the primitive streak and  become committed to mesoderm and endoderm, respectively. We have also identified DNA binding proteins that are involved in priming of regulatory elements for future expression during lineage-commitment and organogenesis.

 

You will subsequently manipulate specific epigenetic factors in ES cells and embryos by CRISPR/Cas targeting and monitor differentiation both in in vitro cell culture and in vivo embryo systems. You will also attempt to manipulate epigenetic states of interesting genes directly by dCas9 epigenome editing, and examine effects on differentiation in vitro and in vivo.

 

You will be part of an interactive and collaborative team in our lab, in the Epigenetics Programme at the Babraham Institute, and in the Single Cell Genomics Centre at the Sanger Institute. This will help you with diverse approaches and techniques such as stem cell and embryo work, single cell sequencing, bioinformatics, computational and statistical approaches, and CRISPR/Cas techniques.

 

There will also be exciting opportunities of asking similar questions about cell fate in human pluripotent stem cells and human embryos, through our collaborations with Peter Rugg-Gunn, Gavin Kelsey, Jenny Nichols and the Wellcome Human Development Biology Initiative.

 

Recent publications

Branco et al 2016 Dev Cell, Angermueller et al 2016 Nature Methods, von Meyenn et al 2016 Mol Cell, von Meyenn et al 2016 Dev Cell, Berrens et al 2017 Cell Stem Cell, Rulands et al 2018 Cell Systems, Eckersley-Maslin et al 2019 Genes Dev, Pijuan-Sala et al 2019 Nature, Argelaguet et al 2019 bioRxiv 519207 Nature accepted

 

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