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Epigenetic regulation of cell fate during early mammalian development

Project description

The role of epigenetics in development

Early on during development, three layers of embryonic cells differentiate to give rise to the vertebrate body. The implicated events are driven by changes in gene expression, but the role of the epigenome remains poorly understood. The EU-funded EpiCellLineage project is working under the hypothesis that lineage-specific genes are epigenetically primed at early developmental stages to ensure transcription. Researchers will investigate the underlying molecular mechanisms and impact of impaired epigenetic priming. The project's results will unveil how the epigenetic landscape impacts cell differentiation during development, shedding light on developmental disorders.

Objective

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan. Single cell RNA-sequencing has identified major transcriptional changes associated with germ layer specification. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell fate choice is poorly understood. We are systematically charting this important developmental progression by single cell multi-omics, tracking simultaneously the transcriptome, DNA methylome and chromatin accessibility. We find that promoters or enhancers of lineage specific genes are epigenetically primed at early developmental stages to safeguard their future transcriptional activation. We have identified DNA binding proteins needed for multi-lineage priming of regulatory elements prior to gastrulation. Here, we will determine the molecular mechanisms of epigenetic priming, and the functional consequences of faulty priming in lineage and organ development. The first objective addresses how the DNA binding proteins DPPA2,4 target chromatin bivalency (H3K4me3 and H3K27me3) to developmental gene promoters, and the consequences of bivalency loss in vivo. The second objective characterises neuroectoderm enhancer priming which occurs already in the early epiblast, and identifies DNA binding proteins and chromatin complexes which prime these enhancers, preparing them for future gene activation. The third objective uses large-scale combinatorial epigenetic editing of promoters and enhancers in vitro and in vivo to determine their impact on cell fate decisions in gastrulation and early organogenesis. This ambitious programme of work will provide fundamental insights into how the epigenetic landscape in early development impacts cell differentiation. Our discoveries will inform strategies for ES or iPS cell based regenerative medicine, and improve our understanding of how developmental disorders arise in humans.

Host institution

THE BABRAHAM INSTITUTE
Net EU contribution
€ 2 351 249,00
Address
Babraham Hall
CB22 3AT Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Research Organisations
Links
Total cost
€ 2 351 249,00

Beneficiaries (1)