Regulation of gene expression via the core promoter and the basal transcriptional machinery

Abstract

The RNA polymerase II core promoter is a structurally and functionally diverse transcriptional regulatory element. There are two main strategies for transcription initiation - focused and dispersed initiation. In focused initiation, transcription starts from a single nucleotide or within a cluster of several nucleotides, whereas in dispersed initiation, there are several weak transcription start sites over a broad region of about 50 to 100 nucleotides. Focused initiation is the predominant means of transcription in simpler organisms, whereas dispersed initiation is observed in approximately two-thirds of vertebrate genes. Regulated genes tend to have focused promoters, and constitutive genes typically have dispersed promoters. Hence, in vertebrates, focused promoters are used in a small but biologically important fraction of genes. The properties of focused core promoters are dependent upon the presence or absence of sequence motifs such as the TATA box and DPE. For example, Caudal, a key regulator of the homeotic gene network, preferentially activates transcription from DPE- versus TATA-dependent promoters. The basal transcription factors, which act in conjunction with the core promoter, are another important component in the regulation of gene expression. For instance, upon differentiation of myoblasts to myotubes, the cells undergo a switch from a TFIID-based transcription system to a TRF3-TAF3-based system. These findings suggest that the core promoter and basal transcription factors are important yet mostly unexplored components in the regulation of gene expression.

Fig. 1

Focused versus dispersed transcription initiation. In focused transcription, there is either a single major transcription start site or several start sites within a narrow region of several nucleotides. Focused transcription is the predominant mode of transcription in simpler organisms. In dispersed transcription, there are several weak transcription start sites over a broad region of about 50 to 100 nucleotides. Dispersed transcription is the most common mode of transcription in vertebrates. For instance, dispersed transcription is observed in about two-thirds of human genes. In vertebrates, focused transcription tends to be associated with regulated promoters, whereas dispersed transcription is typically observed in constitutive promoters in CpG islands.

Fig. 2

Some core promoter motifs for transcription by RNA polymerase II. This diagram is roughly to scale. These motifs are typically found in focused core promoters. There are no universal core promoter elements. It is likely that additional core promoter motifs remain to be discovered. The properties of any particular core promoter are dictated by the presence or absence of specific core promoter elements. For instance, as discussed in the text, a TATA-dependent core promoter with TATA + Inr motifs has different properties than a DPE-dependent core promoter with Inr + DPE motifs.

Fig. 3

Nearly all of the Drosophila Hox genes contain TATA-less, DPE-dependent core promoters. The two most evolutionarily recent Hox genes, Ubx and abd-A, lack both TATA and DPE motifs. Both the upstream (P1) and downstream (P2) promoters of the Antp gene contain TATA-less, DPE-dependent core promoters. In the indicated DPE-dependent core promoters, the Inr and DPE sequences as well as the Inr-to-DPE spacing are conserved from Drosophila melanogaster to Drosophila virilis, which are separated by an evolutionary period of about 40 to 60 million years. lab, labial; pb, proboscipedia; Dfd, Deformed; Scr, Sex combs reduced; Antp, Antennapedia; Ubx, Ultrabithorax; abd-A, abdominal-A; Abd-B, Abdominal-B. Results taken from Juven-Gershon et al. (2008a).

Fig. 4

Caudal is a DPE-specific activator. Caudal preferentially activates transcription from DPE-dependent core promoters relative to TATA-dependent core promoters. In addition, the presence of a BREu motif upstream of the TATA box further suppresses the ability of Caudal to activate transcription. The BREu motif does not affect the ability of Caudal to activate a DPE-dependent core promoter. The TATA box also does not alter the ability of Caudal to activate transcription via the DPE motif (not shown). Results taken from Juven-Gershon et al. (2008a).

Fig. 5

A simplified, hypothetical diagram of activation by DPE- and TATA-specific factors. Transcription factors bind to enhancers, but only activate transcription from promoters with the appropriate core promoter elements. The core promoter containing both TATA and DPE motifs can be activated by either DPE- or TATA-specific activators. Transcription levels can be further regulated by the presence of the BREu as well as other core promoter motifs.

Fig. 6

Replacement of the canonical TFIID complex by a TRF3-TAF3-containing complex upon terminal differentiation of myoblasts into myotubes. Both complexes bind to TATA box motifs via the TBP or TRF3 subunits. These findings exemplify the establishment of a new basal transcription system upon cell differentiation, and suggest that analogous processes may occur in other cell types. Results taken from Deato and Tjian (2007).