1. Introduction

21.1 Introduction

The phenotypic differences that distinguish the various kinds of cells in a higher eukaryote are largely due to differences in the expression of genes that code for proteins, that is, those transcribed by RNA polymerase II. In principle, the expression of these genes might be regulated at any one of several stages. The concept of the "level of control" implies that gene expression is not necessarily an automatic process once it has begun. It could be regulated in a gene-specific way at any one of several sequential steps. We can distinguish (at least) five potential control points, forming the series:

Activation of gene structure

↓

Initiation of transcription

↓

Processing the transcript

↓

Transport to cytoplasm

↓

Translation of mRNA

The existence of the first step is implied by the discovery that genes may exist in either of two structural conditions. Genes are found in an "active" state only in the cells in which they are expressed (see 19 Nucleosomes). The change of structure is distinct from the act of transcription, and indicates that the gene is "transcribable." This suggests that acquisition of the "active" structure must be the first step in gene expression.

Transcription of a gene in the active state is controlled at the stage of initiation, that is, by the interaction of RNA polymerase with its promoter. For most genes, this is a major control point; probably it is the most common level of regulation.

Regulation at subsequent stages of transcription is rare in eukaryotic cells. Premature termination occurs at some genes, and is counteracted by the kinase P-TEFb (see above), but otherwise anti-termination does not seem to be employed.

The primary transcript is modified by capping at the 5′ end, and usually also by polyadenylation at the 3′ end. Introns must be excised from the transcripts of interrupted genes. The mature RNA must be exported from the nucleus to the cytoplasm. Regulation of gene expression by selection of sequences at the level of nuclear RNA might involve any or all of these stages, but the one for which we have most evidence concerns changes in splicing; some genes are expressed by means of alternative splicing patterns whose regulation controls the type of protein product (see 22 Nuclear splicing and RNA processing).

Finally, the translation of an mRNA in the cytoplasm can be specifically controlled. There is little evidence for the employment of this mechanism in adult somatic cells, but it occurs in some embryonic situations. The mechanism is presumed to involve the blocking of initiation of translation of certain mRNAs by specific protein factors.

But having acknowledged that control of gene expression can occur at multiple stages, and that production of RNA cannot inevitably be equated with production of protein, it is clear that the overwhelming majority of regulatory events occur at the initiation of transcription. Regulation of tissue-specific gene transcription lies at the heart of eukaryotic differentiation; indeed, we see examples in 29 Gradients, cascades, and signaling pathways in which proteins that regulate embryonic development prove to be transcription factors. A regulatory transcription factor serves to provide common control of a large number of target genes, and we seek to answer two questions about this mode of regulation: how does the transcription factor identify its group of target genes; and how is the activity of the transcription factor itself regulated in response to intrinsic or extrinsic signals?