TRANSCRIPTIONAL REGULATION OF SELF-RENEWAL IN HUMAN HAEMATOPOIETIC STEM CELLS

Generation of functional HSC from pluripotent cells and robust HSC expansion in culture are limited by our incomplete understanding of the self-renewal process.

My goal is to unveil the regulatory pathways that sustain HSC self-renewal, based on modulation of gene expression at pre- (chromatin modification) and co-transcriptional (transcriptional elongation and RNA polymerase II pausing) levels and as directed by the metabolic state of the cell.

I will carry out my scientific goals with the following aims: - Determine the regulation of HSC self-renewal though modulation of transcriptional rate and RNA polymerase II activity. - Understand the role of HSC metabolism and nutrient availability in the regulation of the HSC self-renewal gene regulation machinery. - Modulate HSC transcriptional regulation to achieve successful HSC generation in culture.

These research avenues will lead to a better understanding of the molecular basis of self-renewal and will provide a foundation to improve the generation and expansion of engraftable human HSCs in culture, in order to fully exploit their potential for clinical applications.

This work will expand our current knowledge of the HSC self-renewal process and provide new insights into the molecular features of stemness, with implications for other tissue stem cells and the cancer field.