Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

384 Chapter 7: Control of Gene Expression
Complex Switches Control Gene Transcription in Eukaryotes
When compared to the situation in bacteria, transcription regulation in eukaryotes
involves many more proteins and much longer stretches of DNA. It often seems
bewilderingly complex. Yet many of the same principles apply. As in bacteria, the
time and place that each gene is to be transcribed is specified by its cis-regulatory
sequences, which are “read” by the transcription regulators that bind to them.
Once bound to DNA, positive transcription regulators (activators) help RNA polymerase
begin transcribing genes, and negative regulators (repressors) block this
from happening. In bacteria, as we have seen, most of the interactions between
DNA-bound transcription regulators and RNA polymerases (whether they activate
or repress transcription) are direct. In contrast, these interactions are almost
always indirect in eukaryotes: many intermediate proteins, including the histones,
act between the DNA-bound transcription regulator and RNA polymerase.
Moreover, in multicellular organisms, it is common for dozens of transcription
regulators to control a single gene, with cis-regulatory sequences spread over tens
of thousands of nucleotide pairs. DNA looping allows the DNA-bound regulatory
proteins to interact with each other and ultimately with RNA polymerase at the
promoter. Finally, because nearly all of the DNA in eukaryotic organisms is compacted
by nucleosomes and higher-order structures, transcription initiation in
eukaryotes must overcome this inherent block.
In the next sections, we discuss these features of transcription initiation in
eukaryotes, emphasizing how they provide extra levels of control not found in
bacteria.
A Eukaryotic Gene Control Region Consists of a Promoter Plus
Many cis-Regulatory Sequences
In eukaryotes, RNA polymerase II transcribes all the protein-coding genes and
many noncoding RNA genes, as we saw in Chapter 6. This polymerase requires
five general transcription factors (27 subunits in toto; see Table 6–3, p. 311), in
contrast to bacterial RNA polymerase, which needs only a single general transcription
factor (the σ subunit). As we have seen, the stepwise assembly of the
general transcription factors at a eukaryotic promoter provides, in principle, multiple
steps at which the cell can speed up or slow down the rate of transcription
initiation in response to transcription regulators.
Because the many cis-regulatory sequences that control the expression of a
typical gene are often spread over long stretches of DNA, we use the term gene
control region to describe the whole expanse of DNA involved in regulating and
initiating transcription of a eukaryotic gene. This includes the promoter, where the
general transcription factors and the polymerase assemble, plus all of the cis-regulatory
sequences to which transcription regulators bind to control the rate of
the assembly processes at the promoter (Figure 7–17). In animals and plants, it
is not unusual to find the regulatory sequences of a gene dotted over stretches of
DNA as large as 100,000 nucleotide pairs. Some of this DNA is transcribed (but
not translated), and we discuss these long noncoding RNAs (lncRNAs) later in
this chapter. For now, we can regard much of this DNA as “spacer” sequences that
transcription regulators do not directly recognize. It is important to keep in mind
that, like other regions of eukaryotic chromosomes, most of the DNA in gene control
regions is packaged into nucleosomes and higher-order forms of chromatin,
thereby compacting its overall length and altering its properties.
In this chapter, we shall loosely use the term gene to refer to a segment of DNA
that is transcribed into a functional RNA molecule, one that either codes for a protein
or has a different role in the cell (see Table 6–1, p. 305). However, the classical
view of a gene includes the gene control region as well, since mutations in it can
produce an altered phenotype. Alternative RNA splicing further complicates the
definition of a gene—a point we shall return to later.
In contrast to the small number of general transcription factors, which are
abundant proteins that assemble on the promoters of all genes transcribed by