Due to its central role for nearly all aspects of life, gene expression is programmed on three different levels:
- the DNA code,
- the epigenetic code and
- the transcription factor program
Gene expression programs.
Gene expression is controlled on at least three levels:
(i) the DNA code, i.e. the sequence of the genome containing the information for coding and ncRNAs and millions of transcription factor-binding sites,
(ii) the epigenetic code, i.e. the combination of the histone code and the rules of DNA methylation and
(iii) the transcription factor program, where the expression and activity of transcription factors depends both on the DNA code and the epigenetic code as well as on extra- and intracellular signals.
Co-factor proteins provide a physical link between the components of the three control levels
Millions of binding sites for the presently 1,900 known DNA-binding transcription factors are distributed throughout the human genome, irrespective if these are intergenic regions, introns or exons. Dependent on their function and position, the regions, where this transcription factor-binding sites are clustering, are called promoters, enhancers, LCRs, silencers or insulators. Most of the genomic DNA is covered by tightly packed nucleosomes, i.e. not readable by transcription factors and RNA polymerases. Therefore, the second level of control of gene expression is determined by the epigenetic code, which is a combination of the histone code and the rules for DNA methylation. Like the DNA code, the epigenetic code is also inherited, but in contrast to the DNA code it is also able to “memorize” major events during the lifetime of an individual, such as a period of famine during embryogenesis. The program of the epigenetic code tightly controls the accessibility of transcription factor-binding sites and also leaves marks for distinguishing active from inactive regions of the genome.
The third level of the control of gene expression is the transcription factor program, which is the relative amount and activity state of the transcription factors that are expressed in a given cell. The expression of transcription factors is controlled by both the DNA code and the epigenetic code. In addition, most transcription factors are regulated in their activity by a number of different processes, such as phosphorylation, ligand-binding, dimerization and translocation. Transcription factors are often the endpoints of signal transduction cascades and in this way they are the nuclear sensors for any type of perturbation of the cell. They do not only bind to their specific DNA-binding sites, referred to as response elements (REs), but homo- and heterodimerize between themselves and also interact with co-factor proteins. These co-factors represent a large family of adaptor proteins, which provide numerous contact possibilities between DNA contacting transcription factors, RNA polymerases and chromatin modifying enzymes. Moreover, also co-factors are in direct contact with signal transduction cascades and are therefore able to sense extra- and intracellular signals. Taken together, all three codes and programs are essential for the control of gene expression and make the process a complex, but highly interesting subject of study.