Endocrine Abstracts

One of the fundamental challenges facing current biology concerns the molecular basis for stem cell formation and behaviour. Haematopoiesis is the best characterised adult stem cell system and continues to provide paradigms of broad biological relevance. The stem cell leukaemia (SCL) gene encodes a transcription factor that is essential for the normal development of haematopoietic stem cells (HSC) and all haematopoietic lineages. Appropriate transcriptional regulation is critical for the normal functions of key regulators such as SCL and yet the way in which regulatory information is encoded in the genome remains largely obscure. Detailed analyses of cis-regulatory mechanisms controlling critical transcription factor genes will be required to understand how transcriptional networks regulate HSC formation and differentiation.

We have used biochemical, genomic, bioinformatic and transgenic approaches to dissect the transcriptional regulation of the murine SCL locus. These studies have resulted in definition of the SCL transcriptional domain, identification of a panel of SCL enhancers, the first molecular characterisation of an HSC enhancer and the identification of a multiprotein complex by which the HSC enhancer is activated. Our results suggest that this complex is responsible for activating SCL transcription and thus establishing the transcriptional programme necessary for the formation of all blood cells.