Orchestrated response: a symphony of transcription factors for gene control

An enormous body of work generated over the past three decades has revealed that eukaryotic gene transcription is a remarkably intricate biochemical process that is tightly regulated at many levels. Biochemical and genetic analysis of various model organisms has identified an astounding number of protein factors responsible for transcriptional control. Although a large assortment of gene-specific DNA-binding regulators was somewhat anticipated, the sheer complexity of the general machinery relative to prokaryotes has been a surprise. Even more unexpected were the numerous and intricate layers of control imposed by the diversification of co-activators and co-repressors, some of which possess enzymatic activities. Many interactions between the identified factors and some of their rate-limiting steps have been discerned. Despite these advances, surprisingly little is known about the detailed mechanisms by which individual genes are turned on or off in a cell. Recent evidence suggests that there is an ordered progression of events leading to RNA synthesis in vivo and that a highly structured eukaryotic nucleus may be important in orchestrating transcription. In this review, we present our interpretation of recent findings and discuss various models that integrate these observations with the emerging elaborate molecular apparatus that has evolved to control gene expression.

Eukaryotic cells carry a tremendous amount of genetic information just to encode the 6000 to 100,000 proteins necessary to perpetuate life from yeast to animals. In addition, genomes must also contain vast amounts of cis-regulatory DNA responsible for directing spatial and temporal patterns of gene expression in response to metabolic requirements, developmental programs, and a plethora of external stimuli. To maintain and control such a large genetic load, eukaryotes have organized co-linear DNA into discrete chromosomes each packaged into chromatin, the minimal unit of which has been defined as the nucleosome (Kornberg 1974; Luger et al. 1997). Variable degrees …