Transcriptional regulation of haematopoietic stem cells

Haematopoietic stem cells (HSCs) are a rare cell population found in the bone marrow of adult mammals and are responsible for maintaining the entire haematopoietic system. Definitive HSCs are produced from mesoderm during embryonic development, from embryonic day 10 in the mouse. HSCs seed the foetal liver before migrating to the bone marrow around the time of birth. In the adult, HSCs are largely quiescent but have the ability to divide to self-renew and expand, or to proliferate and differentiate into any mature haematopoietic cell type. Both the specification of HSCs during development and their cellular choices once formed are tightly controlled at the level of transcription. Numerous transcriptional regulators of HSC specification, expansion, homeostasis and differentiation have been identified, primarily from analysis of mouse gene knockout experiments and transplantation assays. These include transcription factors, epigenetic modifiers and signalling pathway effectors. This chapter reviews the current knowledge of these HSC transcriptional regulators, predominantly focusing on the transcriptional regulation of mouse HSCs, although transcriptional regulation of human HSCs is also mentioned where relevant. Due to the breadth and maturity of this field, we have prioritised recently identified examples of HSC transcriptional regulators. We go on to highlight additional layers of control that regulate expression and activity of HSC transcriptional regulators and discuss how chromosomal translocations that result in fusion proteins of these HSC transcriptional regulators commonly drive leukaemias through transcriptional dysregulation.