Gene Regulation in Eukaryotes

In eukaryotic cells, expression of a gene can be regulated at all those steps we saw in bacteria (Chaptor 16), and a few additional ones besides. Most striking among the additional steps is splicing. As we saw in Chapter 13, many eukaryotic genes come in pieces and, after transcription, the coding region in the RNA is spliced togother to generate the mature message. In many cases, a given transcript can be spliced tn alternative ways to generate different products, and this loo can be regulated.

But just as in bacteria, it is the initiation of transcription that is the most pervasively mgulated step. Indeed, many of the principles we encountered when considering how transcription is regulated in those organisms apply to regulation of transcription in eukaryntes as well. Those principles are laid out in the first few pages of the chapter on prokaryotic gene regulation (Chapter 16) and in the summary at the end of that chapter. We urge readers who have not previously (or recently) read that chapter to look at those passages befnre continuing with this chapter.

We have also already seen that the eukaryotic transcriptional machinery is more elaborate than its bacterial counterpart (Chapter 12). This is particularly true of the RNA polymerase II machinery —that which transcribes protein-encoding genes. Despite ibis added complexity, transcription is once again regulated by activators and repressors— DNA-binding proteins that help or hinder transcription initiation at specific genes in response to appropriate signals. There are, however, additional features of eukaryotic cells and genes that complicate the actions of these regulatory proteins. We begin by summarizing the two most significant of those additional complexities.

Nuclcosomes and their modifiers influence access to genes. As we saw in Chapter 7, the genome of a eukaryote is wrapped in proteins called histones to form nucleosonies. Thus the transcriptional machinery is presented with a partially concealed substrate. This condition reduces the expression of many genes in the absence of regulatory proteins. Eukaryotic cells also contain a number of enzymes that rearrange, or chemically modify, histones; these modifications alter nucleosonies in ways that affect how easily the transcriptional machinery—and DNA-hinding proteins in general—can bind. Thus, nucleo-somes present a problem not laced in bacteria, but (heir modification also offers new opportunities for regulation.

Many eukaryotic genes have more regulatory binding sites and are controlled hy more regulatory proteins than are typical bacterial genes, A further difference between eukaryotes and prokaiy-oles is the number of regulatory proteins that control a given gene. This is reflected in the number and arrangement of regulator binding sites

Conserved Mechanisms of Transcriptional

Regulation from Yeast to Mammals

Recruitment of Protein Complexes to

Genes by Eukaryotic Activators (p 537) •

Signal Integration and CombinakKiai

Transcriptional Repressors (p 549) •

Signal Transduction and the Control of

Transcriptional Regulators {p 551) *

Gene "Silencing" by Modification uf

Eukaryotic Gene Regulation at Steps aftef

Transcription Initiation (p. 562) •

RNAs tn Gene Regulation (p. 567)

associated with a typical gene. As in bacteria, individual regulators bind short sequences, but in eukaryotes these binding sites tire often more numerous and positioned further from the start site of Uanscrip-tion than they are in bacteria. We call the region at the gene where the transcriptional machinery binds, the promoter; the individual binding sites, regulator binding sites; and the stretch of DNA encompassing the complete collection of regulator binding sites for a given gene, the regulatory sequences.

The expansion of regulator}' sequences—-that is, the increase in the number of binding sites for regulators at a typical gene—is most striking in multicellular organisms such as Drosopluio and mammals. This situation reflects the more extensive signal integration found in those organisms: that is, the tendency for more signals to be required to switch a given gene on at the right time and place. We saw examples of signal integration in bacteria (Chapter 16), but those examples typically involved just two different regulators integrating two signals to control a gene (glucose and lactose at the lac genes, for example). Yeast have loss signal integration than multicellular organisms—indeed they are not so different from bacteria in this regard—and their genes have less extensive regulatory sequences than those of multicellular eukaryotes (Figure 17-1).

in multicellular organisms, regulatory sequences can spread thousands of nucleotides from the promoter—both upstream and downstream—and can be made up of lens of regulator binding sites. Often these binding sites are grouped in units called enhancers, and a given enhancer binds regulators responsible for activating the gene at a given time and place. Alternative enhancers bind different groups of regulators and control expression of the same gene at different times and places in response to different signals.

Having more extensive regulatory sequences means that some regulators bind sites far from the genes they control, in some cases SO kh or more. How can regulators act from such a distance? In bacteria we encountered DNA-binding proteins that communicate over a range of a few kb: A repressors at Or( interacting with those at 0(; and NtrC, which can activate the glriA gene from sites placed i kh or more upstream, In those examples of "action at a distance," the intervening DNA loops out to accommodate the interaction between the proteins. The same mechanism explains action at a distance in many, if nut all,

FIGURE 17-1 The regulatory elements of a bacterial, yeast, and human gene.

Illustrated here is the increasing complexity of regulatory sequences from a simple bacterial gene controlled by 3 repressor to a human gone controlled by multiple activators and repressors in each case, a promoter is shown at the ate where transcription is initiated. White tins is accurate for the batlerial case, in the eukaryotic examples transcription initiates somewhat downstream of where the transcription machine binds (see Chapter 12).

bacteria yeas!

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