Gene activation by histone and factor acetyltransferases

336

Gene activation

by histone and factor acetyltransferases

Shelley L Berger Persuasive appear

evidence to truly

transcription

factors

acetyltransferases large, multifunctional

that

to acetylate in viva

acetyltransferases

both

to effect

assemblies, suggest

whose

complex

of GNATS

(Gcn5-related

enzymatic

acetyltransferase

by phosphorylation

activation.

components

In the cell,

In addition,

the first

of HATS have revealed conserved interaction among the superfamily activities

interaction

Finally,

are themselves with

other

regulated

proteins.

Addresses Molecular Philadelphia,

Current

Genetics Program, The Wistar Institute, 3601 PA 19104, USA; e-mail: [email protected]

Opinion

in Cell Biology

1999,

0 Elsevier

Abbreviations CBP ChlP

CREB DNA-PK FAT HAT H DAC PCAF PCIP SAGA

Science

Ltd

ISSN

Spruce

Street,

11:336-341

http://biomednet.com/elecref/O955067401

100336 0955-0674

CREB binding protein chromatin immunoprecipitation cyclic AMP response element DNA-dependent protein kinase factor acetyltransferase histone acetyltransferase histone deacetylase p3OO/CBP associated factor p300/CBP integrator protein Spt-Ada-Gcn5 acetyltransferase

binding

[HDACs]) were previously identified as transcriptional coactivators or corepressors or are novel proteins that possess such gene regulatory activities [Z-4].

of

and

N-acetyltransferases). and

and

as components conserved

functions.

atomic resolution structures mechanisms of acetyl-CoA

histones

gene

have been identified and evolutionarily

macromolecular structures

has emerged

function

protein

Introduction Chromatin structure is generally repressive to interaction of sequence-specific binding proteins with DNA, and thus, nucleosomes must be remodeled in promoter regions during gene activation. Covalent modifications of core histones have long been correlated with changes in chromatin that occur during transcription and replication [ 11. In pardcular, aminoterminal cxtcnsions of the core histones that comprise nucleosomal histone octamers can be acetylated on certain lysine residues, whose positions are nearly invariant through eukaryotic evolution. Acetylation of these lysincs tends co correlate with active genetic loci and, in contrast. these lysines show reduced acetylation at silenced or heterochromatic chromosomal regions. ‘I’here are, two general models to explain the effect of acetyladon. In the first, neutralization of the lysine residues’ positive charge by acetylation lowers the affinity of histone octamcrs for the negatively charged DNA, and in the second, the acetyl groups function as signals for interaction of histones with other regulatory proteins. This field has recently been energized h?; the discovery that enzymes that acetylate histones (histone acetyltrdnsferases [ HATs]) or deacetylate them (histone deacetylases

A large cohort of HATS has been revealed in recent years. The paradigmatic HAT is Shccharom~~ces rermisiue GcnS, largely because it was the first to be discovered and because it has been extensively studied both previously as a transcription factor and currently as a HAT [S]. Yeast GcnS is a member of a closely related family that includes Tem~h.ynzena ~55, human GcnS and human p?M/(:BP associated fidctor (PCAF) [S-8]. Several years ago, yeast GcnS was identified as a transcriptional coactivator. or adaptor, on the basis of its isolation in genetic selectionsfor regulatory proteins affecting DNA-binding activator function. Suhscquent observations established it asa component of a bridging complex - containing Ada2 and Ada3 between activation domains and the TATA-box binding protein (TBP) component of the basal transcriptional machinery [c)]. The subsequent finding that two other well-known coactivators (‘l:df~,2.50and CBP/p.IOO) are also HA% [4] underscores the appealing idea that histone acetylation is an intimate function of the biochemical machinery that is physically targeted to specific promoters to activate them [lo]. In a remarkable parallel experimental development, HDACs were identified and shown to he previously identified transcriptional corepressors[Z]. ‘I’his review focuseson recent evidence providing experimental support for an important role of acetylation of histonesand of transcription factorsduring gene activation in &,v. In addition, great strideshave been made in elucidating the composition of macromolecularcomplexes containing these HATS, which has revealed the biochemical mechanismsunderlying their rolesin transcriptional acti\-ation.

Functional

significance

of HATS in v&o

(:rucial evidence has been obtained that the enzytnatic activity ascribed to HA’lb i77 eitl-o also occurs ill CVW,that this activity is required for transcription. that histone substrates are indeed physiologically relevant, and that histone acetylation results in actual chromatin remodeling. Studies of yeast GcnS and matnmalian CBP/p.iOO used alanine substitution mutagenesisto create mutants used first, to examine HA’I‘ activity i77 ~itl-0 and then to test function in eke. Debilitation of the HA’L’ activity of yeast GcnS correlated

with

lowered

ability

of

CrcnS

to

complement

transcriptional defects caused by deletion of the CCAi gene [I I “,12”]. Importantly, the powerful chromatin immunoprecipitation (ChIP) assay-using antibodies that detect acetylated histones - was employed to show that actttylation of histones in the promoter of a GcnS-dependent gene requires GcnS’s HAT activity [l lo*]. GcnS substitution mutants were also used to demonstrate that

Gene activation

normal nucleosome positioning in a GcnS-dependent promoter requires the &z vitro-established HAT activity [ 13’1. Similarly, mutations that reduce CBP HAT activity also lower the transcriptional activation function of a Gal4-CBP fusion protein in mammalian cells [14]. Taken together, these studies strongly indicate that, in the cell, HATS act upon nucleosomal histones within promoter regions resulting in remodeling of chromatin and activation or repression of transcription. In the past two years, much has been learned about the complexity of interactions in mammalian cells among HATS that function as coactivators for a large group of differentiation-specific transcription factors (including nuclear hormone receptors, myogenic factors, and CAMP responsive factors). The large protein CBP/p300 may function as a platform to assemble an array of coactivators including PCAF, PCIP (p3OO/CBP integrator protein), ,4C’I’R (activator of retinoid receptors), and NuCoA (nuclear co-activator) [8,15,16]. The fascinating observation that each of these coactivators possesses HAT activity raises the question ‘Why so many HATS!‘. One answer may be that, although CBP/p300 recruits multiple HATS, critical HAT activity is contributed by only one of these coactivators. ‘I’hus, MyoD and the retinoic acid receptor require HA’L’ activity contributed by PCAF and not by CBP/p300, whereas CREB requires CBP/p300 HAT activity and not that of PCAF, although both are present at relevant promoters [ 17,181. These data also suggest that the requirement for multiple HATS derives from a need to acetylate multiple substrates, including histones and transcription factors, as described below.

Factor acetyltransferase acetyltransferases

function

of

Provocative in t&-o observations indicate that HATS are capable of acetylating non-histone substrates as well. These include some interesting transcription factors such as the tumor suppressor and DNA-binding activator ~53 [19”], and two basal transcription factors, TFIIE and ‘I’FIIF [ZO]. Recent reports expand these observations to new factor targets (Table 1) and, importantly, show that these targets are physiologically relevant. CBP/p300 acetyTable In viva

histone and factor

acetyltransferases

337

Berger

lates ~53 resulting in increased DNA binding, perhaps by relieving ~53’s intrinsic intramolecular inhibition [ 19”]. p53 is also acetylated by PCAF to increase DNA binding [21,22]. Interestingly, the sites of acetylation of p53 are distinct for CBP/p300 versus PCAF (just as they are for histones; see Table l), although both are in the carboxyterminal negative regulatory region of ~53. Antibodies were developed that detect acetylated forms of the specific target sequences for PCAF or CBP/p300 and were used to demonstrate increased acetylation at both p.53 sites in mammalian cells following irradiation (which causes DNA damage and turns on p53 function) 121,221. Several other transcription factors are now known to be acetylated by HATS (Table l), including two transcription factors, EKLF (erythroid Kruppel-like factor) [23] and GA’I’A-1 (GATA binding protein 1) [24,25], that regulate the hematopoietic cell lineage. In the case of GATA-1. acetylation by CBP occurs, both in vitro and ill U~VO, at lysines adjacent to the DNA-binding zinc-finger motifs. Although the mechanism by which acetylation affects GATA-1 function is still unresolved [24,25], substitution of target lysine residues reduces the ability of GA’I‘A-1 induce erythroid differentiation 1241. Finally, CBP and PCAF acetylate the high mobility group 1 (HMG-I) protein (Table l), the architectural component of the cluster of transcription factors (known as the ‘enhancesome’) that assembles on the enhancer of the IFN-p during viral infection. Acetylation of HMG-1 by CBI’ reduces its binding to DNA, destabilizes the enhancesome and lowers transcription of IFN-p im &-o [26]. The normal shut-off of IFN-P gene expression (which occurs late in viral infection) requires the CBP HA’I‘ domain. In addition, targeted hyperacetylation of histones around the IFN-P promoter occurs early in infection, and requires CBP [27]. Thus, a plausible model is that, during viral infection, the enhancesome recruits CBP to cause a wave of acetylation, first on histones to boost transcription of IFN-P, followed by acetylation of HMG-I to destabilize the enhancesome and reduce transcription of this gene.

1 targets

and regulation

Family

of transcription-related

acetyltransferases. Acetylation targets: nucleosomes

Histones

Gcn5 pSOO/CBP

by

H3>H4 H3 = H4>H2A

MYST

*Increase, decrease denotes either a negative or a positive

Transcription

H3>H2B = H2B

H3 = H4>H2A

H4 the effect of the transcription effect on acetylation activity.

p53 = H2B

H4>H2A factor

on DNA-binding

Enzymatic regulated

factors* (increase)

p53 (increase) HMG-I (decrease) GATA-1 (increase or neutral) EKLF (NK) (NK) activity;

NK indicates

that

effect

Phosphorylation ElA interaction Phosphorylation El A interaction

activity by:+ (neg) (neg) (pas) (neg or pos)

(NW is not

known.

tneg,

pos

denotes

338

Figure

Nucleus

and gene

expression

1

(a)

W

Yeast

SAGA

complex

Biochemical

functions

Acetylation: Activator TBP

Gcn5,

Model of composition of yeast and human GcnB-family protein complexes. (a) A comparison of components of yeast SAGA and human PCAF complexes. The Ada subgroup (AdaP, Ada3, and GcnS/PCAF) is shown in white, with the HAT domain in black; the Spt subgroup (Adal, Spt3, Spt7, Spt8, Spt20) is shown in light gray; the Taf subgroup (TafPO, Taf25, Taf60, Taf68, Taf90 for yeast; Taf20, TaWO, TaMl, Taf55, PAF65a, PAF65b for human) is shown in dark gray; yeast Tral and human TRRAP are depicted as scaffolds for assembly of modules. (b) Proposed functions of members of each subgroup, including enzymatic acetylation, interaction with activators, TBP or promoters and integrity of the complex.

complex

PCAF Ada, Spt,

interaction: integrity:

PCAF

of modules

interaction:

interaction:

Promoter Complex

Human

Taf

Taf Taf

Spt Current

‘Igken together the data suggest that acetylation may be a common modification used to modulate activity of DNAbinding proteins, resulting in either positive or negative effects on DNA binding (‘Ihble l), depending on the location of the acetylated Iysines relative to functional domains. ‘I’here appears to be significant specificity in the sites of transcription factor acetylation. Most interesting is the general possibility that targeted recruitment of HATS by DNA-bound activators results in multiple and site-specific acetylations: on histones to boost gene activity and on other transcription factors resulting in either increased or decreased activity (‘l:dble 1).

Opmon

in Cell Btology

kinase motif of lial/‘l’RRAP is similar in protein sequence to other members of the ATM/DNA-PK family, however, in contrast to other members of the family ?ial/‘l’RAAP appears to lack kinase activity [.37”]. The role of ‘Iial is unknown but clearly phosphorylation is not relevant to its function within SAGA; perhaps ‘Iial provides a scaffold for assembly of the other subgroups into SAGA. A very similar complex, containing analogous groups of transcription factors, has been isolated from human cells using epitope-tagged PCAF (Figure 1) [37”]. ‘I’he striking evolutionary conservation of these two (&S-dependent complexes (Figure 1) suggests great similarity in utilization of EI.K13: in eukaryotes.

Mechanisms A critical area of research to decipher the contexts in which HA’IS operate is the isolation of macromolecular complexes containing these enzymes, identification of other components and elucidation of their functions. Four large HA’I’ complexes were identified in yeast of which two contain (icn.5 [2X’]. A third complex contains Rsal. the first essential HAT identified in yeast [29] which is required for normal cell cycle progression [.W]. ‘I‘he role of the Esaldependent complex, Nu‘44 [ZH’,.30], is not yet known nor are the identities of additional components of the complex. ‘I-he largest of the HA’I’ complexes, the 1.X megaI1alton SA(GA (Spt-Ada-(;cns-acetyltransferase) has been studied in detail (Figure 1). It contains Gcn.5 and is highI>modular in structure and function [28’,31]. ‘I’here are at least four modules, including the Ada subgroup [ZX’J, the Spt subgroup [28’,31], the histone-fold subgroup of ’13s [32”], and ‘lid1 [33-35] - a 350 kDa protein in the Ly’l’hI/I>NA-PK (ataxia-telangiectasia mutated/DNAdependent protein kinase) group of protein kinases. ‘IiaI was initially identified in mammalian cells as a ,%Iyc-interacting protein TRRAP, and was shown to be an essential co-factor for hlyc function [XI]. ‘I‘he carboxy-terminal

Each of the subgroups within SAGA has been previously recognized as being transcriptionally-related in yeast [9,28*]. The subgroups contribute specific biochemical functions: HAT activity, activator interaction, complex integrity, and TBP interaction and regulation (Figure 1) (c),28*,.31]. ‘I’he ‘Iifs present in SAGA and the IY:AF complex are also present in TFIII1 complexes [38], underscoring the notion that these might constitute modules devoted to certain biochemical functions in transcription and shuttled between complexes. The histone-fold motifs within these ‘Ihfs might confer DNA binding to both complexes, as well as TBP interaction and recruitment to the TATA box. In addition. ‘I>f,,(Jl appears co directly interact with yeast activator Gcn4 [.19], however, all available evidence indicates that there are multiple possible interaction points between SAGA and activators, A series of biochemical experiments demonstrated that both yeast SAGA and NuA4 are recruited by specific activators to chromatin templates to acetylate nucleosomes, resulting in gene activation [X,40.41]. ‘I’hus, the biochemical dissection and characterization of these complexes reinforces the initial model [.5] based on the coactivator

Gene

function of Gcn.5 and the Ada proteins [9]: DNA-bound activators recruit the complexes to target HAT activity and recruit TBP to promoter regions. Genetic approaches in yeast have provided insights into the role of HATS in V&W and their interaction with other regulatory complexes. Mutagenesis of lysines in the tails of histone H3 and H4, studied in combination with mutations in GcnS, indicates redundancy in acetylation, suggesting that each lysine is targeted for acetylation by more than one of the acetylation complexes [42]. This may seem paradoxical in light of the specificity discussed above but could bc the case none-the-less and requires further investigation. In addition, synthetic genetic phenotypes occur between (icn.5 and both the Swi/Snf ATP-dependent remodeling complex and the RNA polymerase II mediator complex [43.44], suggesting biochemical interactions between these complexes. Thus transcription is likely to be regulated by orchestrated recruitment of multiple protein complexes having distinct effects on promoter function. Further insights into mechanism of HAT function is provided by two structural studies of the acetyttransferase domains of yeast Hat1 [45], involved in acctylation coupled to replication. and of SmAAT, an aminoglycosidc acetyltransferase from &rr&u marcesc-et1.r[46]. In both cases co-crystals of the HA’I’ domains and acetyl CoA were solved. The similar structures in the regions of interaction suggests that the entire GNAI’ (GcnS-related N-acetyttransferase) family will possess a similar structure to interact with the acetyl CoA. A deeper understanding of the mechanism of catalysis awaits structural determination of the transcriptional related HATS (especially in contact with histone substrates), for which a great deal of functional information is available [ 11“,12”,14].

Regulation ‘I’he identification of the HAT? and HDACs begs the question ‘What controls exist to regulate their activity.“. ‘I’he first regulatory modifications reported are. not surprisingly, caused by phosphorylation. Human GcnS interacts with the Ku DNA-binding subunits of the DNAPK holoenzyme [47]. DNA-PK phosphorylates GcnS to reduce HAT activity both in wife and view, although the overall physiological role of the interaction is not yet known. (:BP is also phosphorylated, specifically at the G, stage of the cell cycle by an unidentified kinase, and this phosphorylation increasesHAT activity [48’]. The SAGA complex may be subject to additional types of covalent modification, such as ubiquitination [49], perhaps to regulate its non-HAT functions. It is likely that other controls are built into these biochemically modular complexes and these will certainly be the subjects of future research. The viral regulator and oncoprotein, adenovirus EIA, also affects HAT activity of CBP and PCAE ElA is mitogenic and promotes growth, at least in part, by interaction with CBP/p300 to lower coactivation of differentiation-specific

activation

by histone

and factor

acetyltransferases

Berger

339

genes [50]. ElA inhibits CBP interaction with PCAF by competing for the same CBP binding sites [8]. Thus, the model was proposed that the PCAF-stimulatory interaction with CBP promotes differentiation, whereas the ElA-inhibitory interaction with CBP promotes mitosis [8]. This mode1 has become confused in recent months by reports of direct binding by ElA to the HAT domains of both CBP and PCAF, resulting in altered enzymatic activity. ‘TWWreports extend the existing model, as they show that El,4 inhibits HAT activity (by an unknown mechanism) [Sl’,SZ]; however, a third paper reports an increase in CBP HAT activity upon interaction with ElA [48’]. It is difficult to understand how the classicactivity of EIA (to promote growth) would be bolstered by activating the HAT activity of CBP (which generally promotes differentiation) and also difficult to reconcile how direct interaction of ElA with recombinant CBP can produce diametrically opposed effects on HAT activity. One explanation is that, as both ElA and the enzymes themselves are acetylated [51’,52], the relative concentrations of the various alternative substrates determine the apparent stimulation or inhibition of HAT activity, when acetylation of histones is assayed.Significantly, a fourth study reports no change in PCAF HAT activity upon ElA binding [53]. Clearly additional studies will be required to dcconvolute these putative regulatory interactions.

Conclusions

and future

directions

Overall this explosive area of researchhas produced novel insights into the direct role of chromatin in gene regulation. And yet there persist many important questions. First, in spite of the progressthat hasbeen made, it is still not clear how acetylation leadsto gene activation. Specifically. do the ionic charge alterations directly change nucleosome/chromatin structure or do the modifications alter interactions of histoncs with other proteins ,? A related question concerns the precise relationship between acetytation and remodeling through the Swi/Snf ATP-dependent complexes. Also, it will he important to determine how widespread FA”T activity is and whether the HDACs are alsofactor deacetylases. What are the functions of the multiple HA’I’ complexes? Do they all regulate transcription, or do some have roles in replication, recombination and other processes?-l-he identification of other complexes and their components should help to resolve this question, as is the case with SAGA. Do transcriptionally-relevant HAT complexes function only to alter chromatin, or do they also function as classical coactivators to recruit basal factors? What is the catalytic mechanism of HATs and is it shared among the families? Given that the groups do not exhibit strong primary sequence similarity in the enzymatic domains, how is specificity achieved in substrate recognition both at the level of the individual HAT enzymes and within the larger complexes? Regulation is still a largely untapped area. The many modules within SAGA suggestthat there may be multiple points

340

Nucleus

and

gene

expression

of regulation, both positive and negative, to augment and attenuate not only HAT activity, but also TBP recruitment. Future studies will continue to expand our knowledge of HA’Ts; moreover, the field will undoubtedly move into investigation of other types of histone modifications, which may work together with acetylation to alter chromatin structure to regulate cellular processes.

Acknowledgements

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A, Yamauchi

MG.

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J, Kotani

T, Prives

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of the purified

C, Avantaggiati

McMahon

SB. Van Buskirk

HA. Duoan

KA. Cooeland

TD. Cole

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VV, Kotani T, Zhang BH, Qin J, Nakatani

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Nataraian

AG: vTAFII61

BM.

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Steger

DJ, Eberharter

A, John

S, Grant

PA, Workman

histone acetvltransferase comolexes stimulate transcription-from preassembled nucleosomal froc 41.

42.

43.

Nafl

Acad

Sci USA

for

1998,

95:i

2924-l

Cell

has a and is required by MO/ Cell 1998,

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