| Humans have 39 Hox genes, which are organized in four gene clusters located on different chromosomes. These genes encode homeodomain transcription factors, best known for their role as master regulators of embryonic development. In addition to this ancestral function, which is highly conserved throughout the metazoan phylum, the mammalian Hox proteins also have important functions in hematopoiesis, in the embryo as well as in the adult. They are involved at all levels of the hematopoietic differentiation hierarchy, including the hematopoietic stem cells, controlling processes like cell fate decisions, differentiation, and proliferation. As such, they are potential targets for therapeutic intervention in various hematopoietic disorders, including leukemias. The main focus of our research is the regulation of Hox gene expression in the hematopoietic system, with the long-term aim of developing strategies to manipulate their expression in a therapeutic context. We are using transgenic approaches in mouse and other model systems to identify the hematopoietic enhancers of the human HOXA cluster, and elucidate the upstream signalling pathways. In addition, we are investigating the molecular mechanisms underlying the cellular "memory function", which acts at the chromatin level to stably maintain Hox gene expression patterns once these are set in reponse to exogenous signals, and which involves the products of the Polycomb and trithorax groups of genes. |
