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Contribution of epigenetic mechanisms to the regulation of transcription during differentiation from the totipotent to the committed states


Differentiated somatic cells derive from the same totipotent cell, they contain the same set of genes, and yet they are extremely diverse in morphology and functions.

How expression of cell-type-specific genes is controlled during the progression from the totipotent embryonic stem (ES) cells to the fully committed cells of the haematopoietic lineages has not yet been studied in detail at early stages of development. Especially little is known about the epigenetic mechanisms that are associated with potentially active (permissive) states in totipotent ES cells and multipotent haematopoietic progenitors.

The proposed work is expected to provide important insights into the epigenetic regulation of transcription during lineage commitment via the investigation of three developmental states:
- totipotent (ES cells),
- multipotent (haematopoietic progenitors), and
- committed (differentiated cells).

As a model system, the complete mouse lambda5-VpreB locus, containing two genes which are expressed in early stages of B cell commitment, will be characterised for epigenetic features that could contribute to the transition from inactive to active states during cell differentiation.

These features are:
- chromatin accessibility and nucleosome structure;
- communication between cis-acting elements in the locus via physical contacts; and
- binding profiles of locus-specific and general transcription factors.

In addition to increasing our knowledge of the mechanism of gene regulation during cellular programming, the work could also improve our understanding of haematopoietic malignancies such as leukaemia.

Part of the project will be achieved in collaboration with other European laboratories that may well raise the quality and attractiveness of the field as well as help establish a competitive independent scientific career for the researcher after the training period.

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