Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

摘要

The nucleus of a eukaryotic cell (which includes plant and animal cells) contains most of the cell’s genetic material in the form of carefully packaged strands of DNA. Genes are stretches of DNA that contain the instructions needed to produce the proteins and RNA molecules that the cell needs to survive. These molecules move across the membrane that surrounds the nucleus through pores made of proteins. One of these pore-forming proteins is called Nup98. The gene that produces Nup98 is frequently mutated in leukemia, where part of it becomes fused to regions of other unrelated genes. The proteins made from these combined genes are known as “fusion proteins”. The Nup98-HoxA9 fusion protein has been well studied, and appears to cause leukemia by interfering with the process called (“cell differentiation”) by which stem cells specialize to form different types of blood cells. During cell differentiation, cells change which sets of genes they activate to become specific types of cells. A family of genes called Hox genes (to which the gene for HoxA9 belongs) is critical in cell differentiation and thus must be fine-tuned. It is also known that the Hox genes form clusters, and its activation is partly controlled by how tightly the DNA is packaged. Previous studies have shown that the Nup98-HoxA9 fusion protein takes on the form of small dots in the nucleus. Oka et al. have now tracked how these proteins are distributed inside of the nucleus, and examined which part of the DNA they bind to, in more detail. This revealed that the dots of Nup98-HoxA9 tend to associate with tightly packed DNA, especially on Hox cluster genes, and activate these genes. Oka et al. further found that a protein called Crm1, which is well known as a nuclear export factor that carries molecules out of the nucleus through the pore, is already bound to the Hox cluster genes in the nucleus and recruits the Nup98-HoxA9 protein. This interaction may change how the Hox gene is packaged in the nucleus. A future challenge will be to reveal how the Nup98-HoxA9 fusion protein and Crm1 on Hox cluster genes control gene expression.