Transcriptional regulators of haematopoiesis

Abstract

The gene encoding the transcriptional regulator Krüppel-like Factor 3 (Klf3) is expressed highly during erythroid development. To investigate its biological role we have been studying a Klf3 knockout mouse model, where loss of Klf3 leads to numerous erythroid defects and mild anaemia. However, this has been complicated by upregulation of the related transcription factor Klf8 in Klf3 null tissue. These two factors are highly homologous and are able to regulate an overlapping set of target genes, suggesting that Klf8 may functionally compensate for the loss of Klf3. In this study, we have addressed this issue by comparing normal, Klf3, Klf8 and Klf3-Klf8 double mutant mouse lines. This approach has allowed us to determine that Klf3 and Klf8 can both contribute to the repression of embryonic globin gene expression during definitive erythropoiesis. Additionally, we have identified an intriguing new Klf3 target gene, a novel short isoform of the master myeloid regulator Pu.1. This isoform, which we have named Pu.2, is expressed via an internal promoter mapping to a retroviral long terminal repeat present in the mouse Pu.1 locus. We have determined that this and other related promoters are regulated by Klf3. Furthermore, we have found that Pu.2 negatively regulates Pu.1 activity and overexpression of Pu.2 in human myelogenous leukaemia cells induces erythroid differentiation. This study concludes that Klf3 plays a key role in erythroid biology that is achieved in part by regulating expression of factors such as Klf8 and Pu.2.