Genomic approaches to understanding Hox gene function.

For many years, biologists have sought to understand how the homeodomain-containing transcriptional regulators encoded by Hox genes are able to control the development of animal morphology. Almost a century of genetics and several decades of molecular biology have defined the conserved organization of homeotic gene clusters in animals and the basic molecular properties of Hox transcription factors. In contrast to these successes, we remain relatively ignorant of how Hox proteins find their target genes in the genome or what sets of genes a Hox protein regulates to direct morphogenesis. The recent deployment of genomic methods, such as whole transcriptome mRNA expression profiling and genome-wide analysis of protein-DNA interactions, begins to shed light on these issues. Results from such studies, principally in the fruit fly, indicate that Hox proteins control the expression of hundreds, if not thousands, of genes throughout the gene regulatory network and that, in many cases, the effects on the expression of individual genes may be quite subtle. Hox proteins regulate both high-level effectors, including other transcription factors and signaling molecules, as well as the cytodifferentiation genes or Realizators at the bottom of regulatory hierarchies. Insights emerging from mapping Hox binding sites in the genome begin to suggest that Hox binding may be strongly influenced by chromatin accessibility rather than binding site affinity. If this is the case, it indicates we need to refocus our efforts at understanding Hox function toward the dynamics of gene regulatory networks and chromatin epigenetics.