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Molecular dissection of transcription factor mediated hematopoietic cell rogramming

Final Activity Report Summary - HEMATOPOIETIC REPROG (Molecular dissection of transcription factor mediated hematopoietic cell programming)

The specialisation of cells, also called differentiation, is dependent on the activation of genes. Transcription factors are proteins that activate genes and thereby drive and regulate differentiation. Since a few years, it was reported that by introducing an 'inappropriate' transcription factor a given cell could be converted into another type of cell. This process is called trans-differentiation or cellular reprogramming.

Both differentiation and reprogramming of cells are still poorly understood on the molecular level. Better and more reliable models explaining these processes would not only be desirable from an academic viewpoint, but could also fuel research in the field of regenerative medicine, i.e. the conversion of one type of tissue into another, referred to as 'tissue regeneration'.

Hematopoiesis, the formation of blood cells, was an excellent system to study the role of transcription factors in cellular reprogramming. Work in our laboratory showed that B-lineage cells could be converted into macrophages by introduction of the transcription factor C/EBPa. In order to study this reprogramming phenomenon in molecular detail we created B cells that contained an inducible form of C/EBPa (C/EBPa-ER). While these cells remained regular B cells, treatment with a hormone led to activation of C/EBPa and subsequent reprogramming of cells into macrophages. By using DNA-microarrays, this system allowed us to conduct a large-scale investigation of all genes that were activated or deactivated during this process. With bioinformatic analyses we identified regulative networks of genes that played a role in cellular reprogramming. These studies greatly extended our knowledge as to how blood cells differentiated and how cellular identity was established by differential gene activation.