Latchman. Eukariotic Transciption Factors

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ACTIVATION OF GENE EXPRESSION BY TRANSCRIPTION FACTORS 171

Figure 5.40

A transcriptional activator

(A) can alter chromatin

structure from a tightly

packed (wavy line) to a

more open (solid line)

structure either (a) by

recruiting the SWI/SNF

chromatin remodelling

complex or (b) by

recruiting a co-activator

(CA) with histone

acetyltransferase activity.

N = nucleosome.

Figure 5.41

In undifferentiated HL-60

cells most transcripts

from the c-myc gene

terminate prematurely at

the end of the first exon.

In differentiated cells,

however, this does not

occur resulting in an

increase in full length

functional transcripts

without increased

initiation.

without an increase in transcriptional initiation (for review see Spencer and

Groudine, 1990; Greenblatt et al., 1993).

Regulation at the level of transcriptional elongation ha s also been demon-

strated in the human immunodeficiency virus (HIV). Thus, in this case only

short prematurely truncated transcripts are produced from the HIV promot er

in the absence of the viral Tat protein. When Tat is present, however, it

stimulates both the rate of initiation of transcription and also the proportion

of full length transcripts which are produced so overcoming the block to

transcriptional elongation (Fig. 5.42) (for review see Greenblatt et al., 1993;

Jones, 1997). A similar role for HSF in stimulating transcriptional elongation

in the hsp70 gene has also been proposed (for review see Lis and Wu, 1993).

Hence activating factors can act to stimulate the proportion of full length

RNA transcripts which are produced.

It has been shown that Tat acts to stimulate elongation by recruiting the

CDK9 kinase enzyme which phosphorylates the C-terminal domain (CTD) of

RNA polymerase II (Kim et al., 2002). As discussed in Chapter 3 (section

3.5.1), phosphorylation of this C-terminal domain is critical for transcriptional

elongation by the polymerase after it has bound to the basal transcriptional

complex. Hence, stimulation of phosphorylation in this way will enhance the

production of full length transcripts (Fig. 5.43).

Such an effect on transcriptional elongation via the CTD of RNA polymer-

ase II is not confined to the viral Tat pr otein but is observed also for cellular

proteins. Thus, as discussed in section 5.4.1, the mediator complex stimulates

the ability of TFIIH to stimulate the CTD, indicating that the mediator can

transmit signals mediating enhanced transcriptional elongation as well as

initiation.

172 EUKARYOTIC TRANSCRIPTION FACTORS

Figure 5.42

The human

immunodeficiency virus

Tat protein stimulates

transcriptional initiation so

that more RNA is made

and also enhances the

proportion of full length

RNA species capable of

encoding viral proteins.

Interestingly, as in the case of transcriptional initiation and the disruptio n

of chromatin, there is evidence that the stimulation of transcriptional elonga-

tion involves activation domains. Thus when binding sites for the yeast tran-

scriptional activator GAL4 were placed upstream of the c-myc promot er, both

the rate of initiation and the proportion of full length transcripts were greatly

stimulated by the binding of hybrid transcription factors contai ning the DNA

binding domain of GAL4 linked to an acidic or non-acidic activation domain

(Yankulov et al., 1994). This effect was not observed in the presence of the

GAL4 DNA binding domain alone or when the GAL4 binding sites were

deleted (Fig. 5.44). Hence the ability of activating factors to act at the level

of transcriptional elongation is dependent on the same activation domains

which act to stimulate transcription at other stages. It is therefore possible for

transcriptional activators to act by enhancing the proportion of full length

ACTIVATION OF GENE EXPRESSION BY TRANSCRIPTION FACTORS 173

Figure 5.43

The HIV Tat protein can

recruit a cellular kinase

which phosphorylates the

C-terminal domain (CTD)

of RNA polymerase

allowing transcription to

proceed.

Figure 5.44

The binding of a

chimaeric transcription

factor containing the

GAL4 DNA-binding

domain linked to an

activation domain

(shaded) stimulates both

transcriptional initiation

and the proportion of full

length transcripts

produced by a c-myc

gene carrying a DNA

binding site for GAL4 (a).

This effect is not

observed when only the

DNA binding domain of

GAL4 is present (b), or

when the GAL4 binding

sites are deleted so that

the activator cannot bind

(c).

transcripts which are produced as well as by stimul ating the number of

transcripts which are initiated (for review see Bentley, 1995).

5.6 CONCLUSIONS

It is clear therefore that acti vation of gene expression by transcription factors

can occur at three distinct stages to stimulate transcription. Thus activating

factors can disrupt the chromatin structure to allow other activating factors

to bind, stimulate the rate of transcriptional initiation so that more RNA

transcripts are initiated and, in some genes, can increase the proportion

of full length transcripts that are produced (Fig. 5.45).

174 EUKARYOTIC TRANSCRIPTION FACTORS

Figure 5.45

An activation domain

(hatched) within an

activating transcription

factor can act (a) by

disrupting the

nucleosome (N)

arrangement of the DNA

so that an activating

factor can bind; (b) by

stimulating the rate of

transcriptional initiation;

and (c) by increasing the

proportion of initiated

transcripts which go on to

produce a full length

RNA.

As described in section 5.5.1, these processes can be combined together in

different ways, for example, in genes modulated by GAGA/HSF and the

glucocorticoid receptor/NFI. An interesting example of this is provided by

the activation of the interferon- (IFN- ) gene by viral infection. Thus, as

noted in Chapter 1 (section 1.3.6), the enhancer of the IFN- gene binds a

multi-protein enhanceosome complex. The binding of this complex (which

includes the DNA binding protein HMGI(Y) and transcriptional activators

such as NFB) to the enhancer is the first stage in the activation of the IFN-

 gene (for reviews see Cosma, 2002; Fry and Peterson, 2002) (Fig. 5.46a).

ACTIVATION OF GENE EXPRESSION BY TRANSCRIPTION FACTORS 175

Figure 5.46

Multi-step activation of

the interferon  promoter

by viral infection. Binding

of the enhanceosome

multi-protein complex to

the enhancer (panel a) is

followed by successive

recruitment of a histone

acetylase (HA) (panel b),

the SWI/SNF chromatin

remodelling complex

(panel c) and finally the

recruitment of the basal

transcriptional complex

leading to transcriptional

activation (panel d).

This enhanceosome complex then stimulates the recruitment of a histone

acetyltransferase complex which acetylates nucleosomes (Fig. 5.46b), allowing

the subsequent recruitment of the SWI/SNF complex (Fig. 5.46c). Further

chromatin remodelling by this complex then displaces a nucleosome exposing

the core promoter, allowing the basal transcriptional complex to bind and

transcription begins (Fi g. 5.46d).

Interestingly, simple displacement of the core promoter nucleosome by

artificial means is not sufficient to induce transcriptional acti vation, indicating

that this multi-step process is required for correct tr anscriptional regulation

(Lomvardas and Thanos, 2002). Similarly, distinc t histone acetylation events

mediate subsequent stages of activation on this promoter. Thus, acetylation of

the lysine at position 8 on histone H4 allows the recruitment of the SWI/SNF

complex while subsequent acetylation of the lysines at position 9 and 14 on

histone H3 allows the subs equent recruitment of TFIID (Agalioti et al., 2002)

(Fig. 5.47). This case therefore illustrates how distinct parts of the ‘histone

code’ (see Chapter 1, section 1.2.3) can mediate the recruitment of different

activating factors, as well as how the two processes of histone modification

and ATP-dependent chromatin remodelling discussed in Chapter 1 (section

1.2) interact with one another to produce transcriptional activation.

Hence, the ordered recruitment of chromatin remodelling fact ors, histone

modifiers, transcriptional activators and the basal transcriptional comp lex is

likely to be crucial for the correct regulation of a variety of different genes,

although the order in which these factors are recru ited is likely to vary for

different genes (for review see Cosma, 2002; Fry and Peterson, 2002).

176 EUKARYOTIC TRANSCRIPTION FACTORS

Figure 5.47

On the -interferon gene

promoter, acetylation (Ac)

of histone H4 on the

lysine (K) at position 8

facilitates recruitment of

the chromatin remodelling

complex SWI/SNF.

Subsequent acetylation of

histone H3 on the lysines

at positions 9 and 14

facilitates recruitment of

the basal transcription

factor TFIID.

A variety of means are theref ore used to activate gene transcript ion invol-

ving modulation of transcriptional initiation, transcriptional elongation and

chromatin structure with a number of factors including components of

the basal transcriptional complex, co-activators, the mediator complex and

chromatin remodelling factors being targeted by transcriptional activators.

Taken together these effects allow transcriptional activators to fulfil their

function and strongly stimulate transcription.

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