Regulation of mammalian gene expression

The expression of mammalian genes is regulated primarily at the level of initiation of transcription. The regulatory structure of the mammalian genes consists of the sequence coding for a protein, a proximal upstream promoter sequence which binds the general (basal) transcription factors and a distant enhancer sequence which binds the inducible transcription factors. The general transcription factors are proteins which combine with the RNA polymerase at the promoter to form the initiation complex. Binding of the inducible transcription factors at short DNA sequences, named response elements, mostly enhances or rarely represses the formation of the initiation complex. Transcription factors share common structural motifs; the most frequent are zinc finger, leucine zipper and helix-loop-helix structures. Inducible transcription factors are activated to bind their target response elements on DNA by protein kinases, by binding of activating or removal of inhibitory factors, or by de novo protein synthesis. Inducible transcription factors are activated by hormones or growth factors addressing a number of genes which share common response elements. Steroid and thyroid hormones combine with intracellular receptors to form active transcription factors. Other transcription factors are activated by protein kinases which are themselves activated by hormones through cell membrane receptors and further cellular signaling paths. Whereas the main level of transcriptional control is the initiation of RNA synthesis, in some instances genes are also regulated by alternative splicing of the primary transcript or control of translation into proteins. Large-scale silencing of genes is mediated by the packing of DNA in highly condensed heterochromatin structures and DNA methylation at cytosines in defined guanine-cytosine (GC)-sequences.