Transcription Factors and Transcriptional Control in Eukaryotic Cells

How did eukaryotic organisms become so much more complex than prokaryotic ones, without a whole lot more genes? The answer lies in transcription factors.

Do complex organisms have more genes than simpler organisms? Now that researchers can sequence whole genomes and have done so for a number of organisms, they know that many vertebrates have only about twice as many genes as invertebrates, and many of these are the result of duplication of existing genes rather than development of new ones. But if there are not that many new genes, what is responsible for the incredible diversity in plant and animal species?

The simple answer to this question is that eukaryotes have developed a more complex way of controlling expression of their existing genes than prokaryotes. This system of expression control relies on a group of proteins known as transcription factors (TFs), and it allows eukaryotes to alter their cell types and growth patterns in a variety of ways. TFs are not solely responsible for gene regulation; eukaryotes also rely on cell signaling, RNA splicing , siRNA control mechanisms, and chromatin modifications. However, TFs that bind to cis -regulator DNA sequences are responsible for either positively or negatively influencing the transcription of specific genes, essentially determining whether a particular gene will be turned "on" or "off" in an organism .

Transcription Factors Recognize Specific DNA Sequences

Topological representation of secondary structure elements in the complex between the NFATC1 transcription factor and its 12-base-pair binding sequence in DNA. The NFATC1-DNA complex shows that NFATC1 is a ten-stranded antiparallel beta-barrel. The two primary sheets (beta-IHFCE and beta-ABG) that form the core of the beta-barrel lie remote from the DNA interface and are almost completely unaffected by being bound to DNA. The third sheet (beta-DG), which does not contact DNA directly but adjoins and abuts multiple segments that do, is also very similar in the free protein and binary complex. The most radical changes that occur upon binding to DNA involve two large surface loops.

© 1998 Elsevier Zhou, P. et al. Solution structure of the core NFATC1/DNA complex. Cell 92, 687–696 (1998). All rights reserved.

Much of the complexity in differentiation in animal and plant cells can be attributed to the evolution of elaborate systems made up of short (6 to 8 base pair) cis-regulatory DNA sequences or motifs, as well as the TFs that bind to the motifs, interact with each other to form complexes, and recruit RNA polymerase II (Levine & Tjian, 2003). Most eukaryotic genes have promoters that consist of the TATA box close to the 5' end of the gene and, farther upstream , several motifs recognized by specific transcription factors. In addition, many genes have one or more other nearby sequences called enhancers. Enhancers affect transcription; these sequences occur upstream, downstream , or within introns, and they continue to work whether in the normal orientation or turned backward in the genome . In yeast , no enhancers are known; instead, there are only upstream activator sequences (UASs). Enhancers can be found thousands of base pairs from a promoter , whereas UASs are generally within a few hundred base pairs upstream. Typical RNA polymerase II promoters can be influenced by many enhancers and by multiple factors bound to the promoter and enhancer sequences.

The mode of action of TFs is to recognize and bind to a segment of DNA in the promoter and/or enhancer region. Often, a change in the conformation , or three-dimensional structure of a TF, will accompany DNA binding. For example, the two loops in NFATC1 that interact with DNA are found in different conformations, depending on whether NFATC1 is complexed with DNA or not (Figure 1). Moreover, the structure of different TF families, described later in this article, results in specific areas in these protein complexes that interact with the DNA recognition motif. The recognition motif is usually only about 6 to 10 base pairs long.

Experiments have shown that TFs can bind tightly, both within cells and in vitro . After TFs bind to promoter or enhancer regions of the DNA, they interact with other bound TFs and recruit RNA polymerase II. Their influence, however, can be either positive or negative, depending on the presence of other functional domains on the protein and the overall impact of the entire TF complex. A typical TF has multiple functional domains, not only for recognizing and binding to the appropriate DNA strand, but also for interactions with other TFs, with proteins called coactivators, with RNA polymerase II, with chromatin remodeling complexes, and with small noncoding RNAs.

TFs control many important parts of development; therefore, organisms with a deletion of a TF gene exhibit profound irregularities in organization and development (Table 1). For example, in Drosophila, deletion of the TF antennapedia gene results in the development of the antennal imaginal disc into legs rather than antennae.

Table 1: Effects of Some Transcription Factor (TF) Gene Deletions in Drosophila