327

Bi, :hirnwa et Btophv.wca A eta, 1088 ( 1991 ) 327- 339 .~5 1 ~gt Elsevier Science Publishers B.V. 0167-4781/91/$03.50 A D.gNIS O167478191001006

BB ~EXP 92233

Review

The regulation of histone gene expression during the cell cycle Nathaniel Heintz Howard Hughes Medwal Institute, The Rockefeller UmversJO'. Ne~ York, N Y ( U. S.A~) (Received 8 January 1991)

Key words: Histone gene expression; Cell cycle; Transcriptional control

Contents I.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

327

II.

Control of histone synthesis during S phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Histone gene promoters and transcriptional control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Factors regulating histone gene transcription during S phase . . . . . . . . . . . . . . . . . . . . . . . . . I. OTFI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. H I T F I and H I T F 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. H4TF2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

328 328 331 331 332 333

Ill.

A model for histone gene transcriptional control during S phase . . . . . . . . . . . . . . . . . . . . . . . . .

334

IV. Posttranscriptional control of histone m R N A abundance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Histone m R N A sequences involved in posttranscriptional control . . . . . . . . . . . . . . . . . . . . . . B. Processing of the histone 3' terminus and the cell cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

335 335 336

V.

337

The regulation of histone m R N A stability during the cell cycle . . . . . . . . . . . . . . . . . . . . . . . . .

VI. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

337

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

338

I. Introduction

Over two decades have passed since Robbins and Borun [1] first discovered that histone proteins are synthesized at significant rates only during the S phase of the cell cycle. This observation raised several issues of fundamental importance for understanding the periodic expression of histone genes and provided an enticing avenue toward understanding the biochemical and

Abbreviations: CP, core promotor; SSCS. subtype specific consensus element; DAD, distal activating element. Correspondence: N. H e i n ~ Box 260, Howard Hughes Medical Institute, The Rockefeller University. 1230 York Avenue, New York, NY 10021-6399, U.S.A.

molecular events which constitute the transition from the G1 to the S phase of the cell cycle. In this review. 1 will discuss the principal experimental basis for our present understanding of molecular mechanisms regulating histone gene expression. Particular emphasis will be given to the following issues: the nature of the mecharhsms for S phase specific expression of histone genes; the coupling of histone gene expression and DNA synthes,s; processes controlling the coordinate and stoichiometric production of histones during S phase; and the ability of the cell to titrate histone production to that quantity required for chromatin assembly. This is not intended as an exhaustive review of the field, but as a brief discussion of the issues confronting it, their general biological significance and the experimental evidence supporting our current understanding of these issues.

328 II. Control of histone synthesis during S pha~,e

Early investigators in this field used a variety of techniques to establish that the S phase dependent synthesis of histories resulted from an increase in histone mRNA concentration, and that this was most likely due to both transcriptional and posttranscriptional processes [2]. Isolation of histone gene clones from a variety of species provided the necessary tools to measure directly tee accumulation and rate of synthesis of histone mRNA during the cell cycle in many different systems, These studies confirmed the expectation that histone mRNA accumulation is regulated by both transcriptional and posttranscriptional mechanisms [3,4], that these mechanisms are dynamic and can be activated rapidly and reversibly multiple times during a single S phase [4], and that the approximate 20-fold increase observed during S phase occurred in a variety of eucaryotic cells from yeasts to mammals. Although these general statements are on very solid experimental footing, it is pertinent to mention that the observed relative contributions of transcriptional vs. posttransciptionai mechanisms to histone mRNA accumulation may vary significantly depending on the system utilized or the method of analysis. For example, although the rate of transcription of replication dependent historic genes during S phase is commonly cited at approx. 3-10-fold that measured in GI [5,6], this must be viewed only as a rough minimal estimate. This derives from the fact that the actual amount of incorporation of radioactive precursor into histone mRNA during G1, as measured by hybridization of in vivo [3H]uridine pulse labeled RNA or by [32p]UTP nuclear run on analysis, is not grossly elevated over background hybridization to - 65

- 100

H4 TFI

~9

~C b o x l e c t o r , HITF~ L

HITFZ ~

SP 1

J D I s l o l OCtlvotmg ~0 rnotn

i1-,4. Histone gene promoters and transcriptional control During the past several years, a variety of both in vivo and in vitro studies have demonstrated that increased transcription of histone genes during S phase is regulated through promoter proximal DNA sequences and their cognate transcription factors. In animal cells, transfection analysis of histone H4 [7], H3 [8], H2b [9,10] and HI[I 1] promoters has clearly established that each of these gene types requires quite limited 5' flanking sequence for correct S phase regulation of transcription. Furthermore, directed mutagenesis of these pro- 35

$PI

CBP.

the plasmid only control [3,4]. Thus. very small changes in the background subtracted in the GI sample can have quite a large effect on the observed relative change in transcription rate. Furthermore, this background may derive in large part from transcription of non-replication dependent histone gene variants. Taken together, these considerations allow for the possibility that the actual rate of transcription of a single replication variant histone gene may increase substantially more than 3 10-fold during S phase. Similar problems arise in obtaining direct and accurate measurements of the half-life of histone mRNA, precluding quantitative and definitive statements concerning the contributions of transcriptional and posttranscriptionawmechanisms to cell cycle control of histone mRNA abundance. This contributes to the disagreement over their relative importance in achieving proper regulation, although it does not detract from the essential fact that a molecular description of these regulatory processes will be extremely valuable for understanding the G1 to S phase transition.

+1

H4TF2

TF II D

O T F I ( N F m . OCt I)

";F ]I D

H1 T F 2

TF li D

I

IL S u b t y p e speclhc con 5tLnsu5 Sequer)ce

Fig. 1. Organizational similarity of the mammalian histone

, Core p r o m o t e r

114, H2b and HI gene promoters. General domain structure of the three promoters is indicated. Abbreviated names of transcription factors known to interact with these promoters are also shown, and further explained in the text.

329 moters has demonstrated that the individual elements critical for cell cycle control are not shared by genes encoding different histcne subtypes. Rather. induction of histone gene transcription during S phase is due to subtype specific consensus elements which ar-" highly conserved in position, orientation and sequence within a specific histone gene family. An illustration of histone gene promoter stucture is given in Fig. 1, which diagrammatically depicts the organization of histone H4. H2b and HI promoters. In these genes, subtype specific sequences which contribute to cell cycle control are present in virtually every H4, H2B and H1 gene so far isolated from a variety of higher eucaryotes (see Ref. ! 2 for review). Although the individual elements which regulate these promoters are distinct, a general organizational paradigm can he constructed which has imp!ications for understanding the mechanism of transcriptional control. A typical histone gene promoter can be construeu as consisting of three fundamental units: the core promoter (CP), the subtype specific consensus elements (SSCS) and the distal activating domain (DAD). The CP is simply those minimal sequences necessary and sufficient for proper initiation by R N A polymerase II. In general, the C P is composed of the T A T A box and the initiator element which are both crucial for setting the position and rate of transcription initiation (see Ref. 13 for review). Thus, deletion of sequences in the region of the histone H4 C A P site can have rather dramatic effects on the initiation of transcription in vitro [14], whereas similar mutations have very little or no effect on H2b transcription [15]. In the case of histone genes, the core promoter is not thought to contribute to cell cycle control, although a direct test of this has not been done since mutation of the T A T A box results in a complete inhibition of transcription.

The distal activating domain (DAD) ill this model of histone gene promoters is comprised of those upstream promoter elements which are constitutivdy active during the cell cycle. In the simplest case (e.g., the H4 and H2b promoters) these sequences are located beyond approx. - 7 0 bp, and are variable be:wcen individual members of a given gene family. D,Aetion of these elements typicall) results in about a 20-fG.d decrease in transcription [9i. Although these sequences do not appear to be the primary determinants of cell cycle regulation, the spec;fic sequences present in the distal activating domain may in some cases contribute to this process [10]. A more general role for these sequences can be envisaged based on the variability and nature of the elements present in the distal activating domain of different genes within a given family and the quite different levels of expression of each family member in a ~pe~ific cell. Thus, one might speculate that the major role for the D A D is to determine which member of each family will be the major producer of that type of histone in each cell type [16]. In this case, the D A D can be viewed as a continental control element which can influence the choice of histone gene family member to be maximally expressed in a particular class of cell based on the transcription factor milieu present. It seems probable that the choice of element present in this region of the promoter is somewhat restricted, since it must not dominate cell cycle control by the subtype specific elements but must provide for robust expression during S phase in concert with the regulatory elements. Variation in the nature of the distal activating domain in the different copies of each of the dozen or so histone genes encoding each histone subtype may ensure global production of histones in all dividing cells of complex higher eucaryotes. The transcriptional induction of histone genes upon

Transcription Factor

Sabtype. Specific Consensus

Species Included

H4TF2

TC'VrCAGG'I~rCTCAGANNGGTCCG CT T AT

Human H4 genes

OTF-1 (oct-l)

CCTNA'ITFGCATAC T

Avian, Mammalian H2b

H1TF1 (AC Box Factor)

AAGAAACACAAA C

Avian, Mammalian HI

H 1TF2 (HiNFB(?))

GCACCAATt ACAGCGCG C Avian, Mammalian H1 C G Fig. 2. Compilation of subtype specificconsensus sequences bound by histone ge~netranscription factors thought to regulate tran~-ription during S phase. Sequence comparisons were based on published histone gene sequencx's[12.39.69]. except in the case of H4 genes. The H4 consensus v.a~s derived from five human histone H4 ~quences which have not yet been published [17] because this etement shows significant divergence in cr~ss speoes comparisons.

330 entry into S phase has in several cases been directly demonstrated to be effected through the subtype specific consensus elements [8 11]. As shown in Fig. 2, these element:, are typically 12-16 nucleotides long and may contain core consensus elements which are present in a wide variety of geoe~_ For example, the H2b and HI proximal SSCS contain core octamer and CCAAT sequences, respectively. The H1 distal SSCS (the AC box) and the H4 proximal SSCS on the other hand, do not appear to be widely distributed among RNA polymerase I1 promoters. The presence of such common core elements in some of the SSCS raises important issues that have only partially been resolved. Most notably, it is not yet clear whether the extensive conser~ation beyond these core domains is crucial for selection of a particular member of a transcription factor family, or a particular species of a given factor, for activity on histone gene promoters, or whether the specific sequence context for these core elements might influence the functional properties of a general factor to effect cell cycle control (see below). It is particularly germane that these elements are extremely consistently positioned relative to the core promoter. Thus, the distance between the proximal histone subtype specific elements depicted in Fig. 1 and the TATA box does not typically vary greater than 1 bp and the orientation relative to the core promoter is maintained in spite of the fact that these genes have been independently evolving since before the radiation of mammals and birds [16]. It appears certain, therefore, that the precise juxtaposition of these elements with the core promoter may reflect an important functional interaction, possibly involving the TATA binding transcription factor TFIlD. The most important property of the subtype specific consensus elements, however, is their direct participation in S phase specific transcription. Tbis has been particularly well documented for the histone H2b and H1 promoters. In the case of the histone H2b promoter, fusion gene constructs containing variable 5' flanking sequences or directed point mutations were assayed in synchronized cells utilizing a transient expression protocol [9]. Deletion of all sequences upstream from lhe subtype specific element resulted in drastic decreases in transcription efficiency relative to a cotrar,fected internal control gene, but haa no effect on the increased transcription of the H2b gene upon release into S phase. In contrast, point mutations which inactivate the H2b octamer element eliminated the S phase specific induction of transcription without altering the level of transcription prior to entry into S phase. These experiments established that the H2b subtype specific consensus elemenl is necessary and sufficient for programming S phase specific activity of the H2b core promoter. They also demonstrated that the H2b subtype specific element is specifically utilized only during S phase in

cycling cells, since its inactivation lay mutagenesis did not result in decreased transcription prior to release into S phase. Thus, the H2b SSCS can be considered a true cell cycle regulatory element which is active only during the S phase of the cell cycle. Subsequent studies have suggested that sequences present in the distal activation domain of a rat testis histone H2b gene, in addition to the SSCS, contribute to cell cycle control [10]. In this case, deletion of the upstream CCAAT box decreased S phase induction approximately fifty percent. Thus, although the H2b SSCS is sufficient for S phase regulation of somatic replication dependent histone H2b genes, its activity can be influenced by other promoter elements. The involvement of SSCSs in S phase specific transcription has also been very well documented in the case of histone HI genes. Thus, deletions or point mutations of the H1 distal SSCS in a chicken HI promoter severely depress S phase transcription after transfection into human cell lines [11]. Furthermore, deletion of this element (the AC box) strongly diminishes cell cycle regulation of the H1 promoter in extracts prepared from centrifugally elutriated cells at various points in the cell cycle [17]. Point mutations which inactivate the HI proximal SSCS (the CCAAT box) also severely and specifically depress S phase transcription in vitro without influencing transcription from a non-cell cycle regulated internal control gene [17]. These results not only identify SSCSs as crucial control elements in the HI promoter, but support the paradigm for transcriptional control of histone genes which was first formulated on the basis of the H2b experiments (see Fig. 1). Furthermore, they predict that the H4 SSCS will be critical for S phase expression of the H4 gene family, although a direct test of this prediction has not yet been accomplished. It is not yet clear whether the histone H3 and H2a vertebrate gene families are also described by this general model. In neither of these cases has inspection of promoter sequences revealed a similar highly conserved sequence element of the type found in H4, H2b and HI genes. In depth analysis of the regulation of a hamster histone H3 gene after transfection into the K12 ts cell line has located a 32 bp region approx. 180 nucleotides upstream from the CAP site which is required for high level expression and cell cycle regulation [8]. While it is apparent thai this element contributes to cell cycle control, further analysis will be required to determine whether other promoter elements in the H3 gene are also important for S phase induction of transcription. Since a thorough examination of H2a cell cycle regulatory elements has not been done, it remains an open question whether DNA sequences that are functionally equivalent to the H2b and HI subtype specific consensus sequences, but perhaps much less well conserved, are involved in H3 and H2a transcriptional control.

331 The utilization of subtype specific S phase regulatory sequences arose quite late in the evolvtmn of histone gene families. In several lower eucaryotes [18-20] and in plants [21] a single histone specific consensus sequence is present and shared by all members of the gene family. Regulation of Saccharomyces cerevisiae histone gene expression during the cell cycle has been especially well characterized [18]. in S. cerevisiae, there are eight histone genes (two each encoding the four core histones) arranged as non-allelic, divergently transcribed pairs of H2a-H2b and H3-H4 genes [22,231. Regulation of the H2a-H2b gene pair (HTA-HTB1) has been extensively studied and has resulted in the identification of both positive and negative promoter elements [18]. The S phase activating sequence of this histone gene pair consists of a 16 bp consensus sequence which is repeated three times in the intergenic spaces, and which can confer S phase specific transcription on a heterologous gene [18]. Tiffs element is present in the intergenic spacers of all four pairs of S. cerevisiae histone genes and it is presumably responsible for coordinate activation of all these genes at the G 1 / S phase boundary. It is probable that the highly conserved elements found in S. pombeii [191, C. elegans [201 a,id wheat [21] histone genes also subserve the S phase specific positive regulatory role described for the S. cerevisiae sequence. One might consider these highly conserved regulatory elements as the evolutionary predecessors of the mammalian SSCSs. The S. cerevisiae HTA1-HTB1 intergenic sFaces also contains a negative regulator' ele~pet:t which results in overproduction of both H2a and H2b mRNA if deleted [18]. This negative control element appears to be important for maintenance of prope, stoichiometric production of histones [24]. Three :~,ms~.:;og mutations which act through the negative regulatory element have been identified [251 although the p. ~uucts of these genes and their mechanisms of action remain unknown. It is of considerable interest to determine whether the autogenous regulatory r~e '~:amsm describea in these studies of S. cereoisiae histone gt ~ transcription persists in higher eucaryotes, or w,~ .~'~r its role has been allocated exclusively to posttranscriptional mechanisms. No convincing demonstration of a functionally similar negative control element in histone promoters from higher eucaryotes has yet been reported. The evolution of subtype specific regulation of histone gene expression in higher eucaryotes from its similar but simpler predecessor in lower eucaryotes presents an interesting problem: why bother with this added complexity in a regulatory switch whose final goal (increased production of histones during S phase) is the same? Although no clear answer to this qt.ery is y"t available, it must certainly rest upon the simple fact that histone production and regulation is essential in every dividing eucaryotic cell. Presumably, the increased

complexity of cell types found in higher animal species is the driving force for evolution of the additional regulatory complexity of the histone gene superfamily [16]. As mentioned above, the existence of independently evolving histone genes with divergent promoter structures may reflect the inability for a sin~e promoter to provide appropriately regulated histone production in all cell types. Furthermore, the ability to regulate production of each histone subtype independently may accomodate the evolution~" !'~stability of histone gene copy numbers in this rapidly evoL'!,ag gene family. It seems reasonable, thereeore, to propose that the unusual requirement for very rapid and stoich~ometric production of histones during S phase, the multitude of different cell types in higher animals and the changing composition and activity of transcription factors present in these various cells all contribute to the evolution of additional regulatory complexity in the histone gene family in higher eucaryotes. ll-B. Factors regulating histone gene transcription during S phase A great deal of effort has been expended to identify transcription factors which are important for the expression of histone genes. The focus of this discussion will be those proteins known to contribute to S phase specific transcription of histone genes and the mechanism{s) for activating these proteins upon entry into S phase. II-B.I. OTFI The best studied factor known to be directly involved in cell cycle control of histone transcription is OTFI (also called NFIII and octl). This factor was originally identified as an approx. 90-95 kDa protein present in HeLa nuclear extracts which binds to the core octamer motif in the H2b subtype specific consensus sequence, and which can specifically stimulate histone H2b transcription as much as 20-fold in vitro [26]. Subsequent studies demonstrated that OTF1 is functionally identical to N FI I I [27], a cellular factor involved in adenovirus DNA replication in vitro [28,291. It ~.~s now been demonstrated by direct protein sequence analysis of OTF1 that it is identical to octl, a protein which was originally cloned due to its ability to specifically bind to the SV40 enhancer [30]. Analysis of the deduced amine acid sequence of octl revealed that, in addition to a 7,onsensus homeodomain, the octl gene carries a novel protein motif named the POU domain, since it was first identified by comparison of the Pitl, octl and Uric 86 DNA binding proteins [30]. Functional dissection of octl suggests that the POU/homeodomain is u.~ . d for DNA binding [311. The fact that the e~l~ression of cloned octl does not transactivate try, ; o n of mRNA encoding promoters in in vivo ~:,~:.ansfection

332 assays has precluded identification of the transcriptional activating domain of octl [32]. Although complex models explaining this result have been offered [32]. interpretation of the experimental results is complicated by the distinct possibility that the cloned octl protein used in these assays does not encode the entire Nterminus of the protein. This type of analysis has not yet yielded significant insights into domains of octl which might be specifically involved in S phase specific transcriptional activity. The octamer dependent DNA binding and in vitro transcription activity of OTF1 on the H2b promoter [26] has stimulated a number of studies to determine whether its DNA binding changes during the eucaryotic cell cycle. In actively cycling cells synchronized by drug treatments [11] or centrifugal elutriation [17], the DNA binding activity of OTF1 does not significantly increase upon entry into S phase. Since the increase in histone gene transcription in vivo [33] and in vitro as cells enter S phase under these condtions is as great as that seen by other synchronization protocols, the provisional conclusion from this work in that increased DNA binding by OTF1 during S phase is not responsible for its ability to activate transcription. However, it is quite clear from biochemical analysis of OTF1 that it is in great excess over other histone cell cycle regulatory proteins. Furthermore, it quite clearly has a role in other (presumably non-cell cycle regulated) transcription events [34]. Thus, these measurements of bulk OTF1 binding may mask significant variations in DNA binding activity of specialized subpool of this factor used exclusively for histone gene transcription or other S phase specific events. In contrast, OTF1 DNA binding can increase during the transition from GO to S phase in serum stimulation protocols [35]. Since this increase is evident in serum stimulated cells which have been arrested at the G 1 / S border that do not exhibit increased histone gene transcription in vivo, it is apparent that this is a separate regulatory mechanism to provide protein for its subsequent transcriptional activation upon entry into S phase [17]. Decreased DNA binding activity is observed for several transcritpion factors under conditons of serum arrest [17], perhaps reflecting a more general regulatory mechanism not reserved for those factors temporally regulated in actively cycling cells. To gain further insight into the mechanisms regulating OTF1 transcriptional activity during the cell cycle, specific antibodies have been prepared and utilized to examine its properties in synchronized cell populations (Roberts, S.D., Segil, N. and Heintz, N., unpublished data). Neither the abundance of OTF1 nor its rate of synthesis vary significantly during the cell cycle. However, immunoprecipitation of OTF1 from cells which have been pulse labelled with [J2p]orthophosphate has revealed that it is regulated by posttranslational modification as cells progress through the cell cycle. At least

nine different forms of OTF1 can be resolved by twodimensional electrophoresis. The subset of these forms which are present in the cell changes as cells transit the cell cycle. Peptide mapping experiments have confirmed these results, revealing at least 11 distinct phosphopeptides. As expected from the two-dimensional gel electrophoresis studies, the distribution of phosphopeptides observcd also changes as cells progress toward division. Two recent studies provide insight into the possible consequences of OTF1 modification. DetaiJed analysis of the domains of octl required for binding to several of its well characterized binding sites has revealed that both the homeo domain and the POU-specific domain are involed in DNA binding and that the POU-specific domain contributes both affinity and specificity to the intrinsic DNA binding capacity of the octl homeo domain [37]. It follows that modifications in the POU domain could potentially alter the DNA binding properties of octl sufficiently to direct it to different target binding sites. A further suggestion that this type of functional modification might pertain in vivo is provided by the analysis of Xenopus octl DNA binding specificity during early development (Byars, D., HinkIcy, C. ~nd Perry, M., unpublished data). Thus, the DNA binding properties of Xenopus octl as measured using a consensus octamer binding site are similar in both oocyte and embryonic cell extracts. However, if one assays octl DNA binding activity using a variant octamer sequence present in the Xenopus H2b genes, greatly enhanced activity is found in the embryo extracts. It appears, therefore, that the binding specificity of Xenopus octl is developmentally regulated, presumably by posttranslational modification. Thus, these studies provide a first glimpse into the types of functional consequences one can foresee for the myriad forms of this interesting transcription factor.

II-B.2. HITFI and HITF2 As discussed above, cell cycle regulation of histone H1 transcription is accomplished through the agency of two separate subtype specific consensus sequences [11,17]. Factors interacting with each of these elements have been described [11,39]. Initial studies of factors involved in histone HI transcription concentrated on the HI AC box, which is the most highly conserved element in the HI promoter [12]. Its cognate D N A binding factor has been termed the AC box factor [11] or H1TF1 [39]. Assays of the DNA binding activity of this factor during the cell cycle do not agree with one another. It was initially reported that binding to the AC box characteristically increases when cells are released into S phase following a single step synchronization with aphidicolin [11]. In these experiments OTF1 DNA binding did not change upon entry into S phase. Subsequent assays of the AC box factor (H1TF1) in centri-

333 fugally elutriated cell populations reported that its DNA binding activity did not change during the cell cycle [17]. However, further analysis of the putative AC box factor assayed in this second study have revealed that it does not bind all histone HI AC boxes and is not, therefore, the HI specific factor of interest (Segil, N. and Heintz, N., unpublished). Thus, it remains quite probable that the original study is correct, and that the AC box factor does increase in DNA binding as cells enter S phase. Until this factor is properly characterized definitive statements with regard to its biochemical activities during the cell cycle can not be made. In contrast to the HI AC box factor, the HI proximal subtype specific DNA binding protein (H1TF2) has been extensively characterized [39]. H1TF2 is a CCAAT binding protein of approx. 45 kDa which can be purified to homogeneity as a single polypeplide which retains specific DNA binding activity [39]. This protein is not active in in vitro transcription assays suggesting that full functional activity of H1TF2 may require additional polypeptides. This is not particularly surprising, given that other characterized CCAAT binding factors are multimeric [40-42]. It is quite possible, 1or e×a:-,iple, that H1TF2 and HiNFB [43], a multimeric protein which also binds the HI CCAAT box, are identical and that they might be related to other mammalian C C A A T binding factors. Thus, it is not yet clear whether the H1 SSCS's role in the cell cycle is achieved utilizing a protein factor which is specifically committed to HI gene expression or, as in the case of H2b regulation, it involves a specialized function of a more general transcription factor analagous to octl. It is probable, however, that HITF2 is the cognate protein for the HI proximal SSCS. This conclusion derives from the fact that H1TF2 DNA binding activity increases during the cell cycle in parallel with histone HI transcription [17]. This is quite an interesting funding, given the observation that bulk OTF1 DNA binding activity is not cell cycle regulated (see above). Antibodies specific for H1TF2 have recently been obtained (Martinelli, R. and Heintz, N., unpublished) and are presently being employed to study this factor during the cell cycle. It will be particularly important to determine whether its phosphorylation state changes during the cell cycle as does OTF1, supporting the idea of single pleiotropic regulatory step for the coordinate transcriptional regulation of histone gene expression [9]. H-B.3. H4TF2 The final candidate for a histone gene S phase transcriptional regulatory factor is H4TF2 [44]. Although no direct evidence is available to prove that the H4SSCS is responsible for S phase transcriptional induction, its similarity to the H2b and HI SSCSs suggest this as a very likely possibility. A 60 kDa protein which specifically binds the H4 SSCS and specifically stimulates

histone H4 transcription in vitro has been extensively characterized [44]. It is quite certain that this factor participates in H4 transcription, since it binds with high affinity and specificity to five different human histone H4 genes. Two of its biochemical properties are particularly interesting. First. its DNA binding and transcription activites are dependent on the presence of Zn 2+, suggesting that it is a Znz÷ finger protein [45]. Thus, if its activity is coregulated with octl, that regulatory scheme must be able to recognize as substrates proteins from completely different transcription factor families. Second, H4TF2 DNA binding activity is present at less than 5% of octl and H1TF2 DNA binding activity (Dailey, L., S. Roberts, S. and Heintz, N., unlrublished). This suggests that this factor may be committed to histone H4 transcriptional control exclusively, in contrast to the multiple functional roles within the cell subserved by octl. Although the very low activity of this factor in the cell has made its analysis quite difficult, it may be particularly useful to focus additonal attention on it. For example, it has been reported that introduction of > 35 copies of the human histone Hu4A gene into mouse L cells results in complete shut off of endogenous mouse H4 gene expression [7]. If this reflects in vivo titration of the H4TF-2 transcription factor, it supports the speculation that this protein is used exclusively for H4 tkanscription. If this is indeed the case, it may provide a p -ticularly clear system for analysis of histone gene trans~ ~-iptional control in vivo. Finally, assays of H4TF2 DNA binding during the cell cycle have not detected increased activity during S phase (Dailey, L., Roberts, S. and Heintz, N., unpublished). This is consistent with the demonstration that the H4SSCS remains bound by protein in vivo during all phases of the cell cycle [461. A second DNA binding factor has been reported which specifically interacts in the vicinity of human FO108 histone H4 SSCS [47]. This protein, I-/iNFD, is definitely not related to H4TF2, since its migration on DNA in native gels, its chromatographic properties and its sensitivity to chelation of divalent metal ions with 1,10-phenanthroline are all distinctly different [47]. It is appropriate to ask which of these putative H4SSCS binding proteins is relevant to transcriptional control in vivo. Although no definitive answer to this query is yet available, it seems obvious that the factor regulating the H4 gene family should bind to all of the H4 genes. No evidence regarding the binding of HiNFD to H4 genes other than FO108 has been reported. I'~ is ~ossible, therefore, that HiNFD is not a general H4 transcription factor and may not be relevant to transcriptional control of the majority of H4 genes. Resolution of this important issue will require the purification and characterization of HiNFD and further analysis of its potential role in FO108 histone H4 transcription. Two studies supporting a role for HiNFD in cell

334 cycle regulation are of particular interest. The first reports that HiNFD DNA binding activity is present throughout the cell cycle in undifferentiated HL60 cells, but is lost upon differentiation of these cells in response to TPA [48]. This correlates with the occupancy of the H4 SSCS in HL60 cells in vivo [48], suggesting a causative relationship. A second study extends this line of investigation into other transformed and non-transformed cell lines. It is reported that binding of HiNFD is constitutive during the cell cycle in transformed cells, but that its DNA binding is cell cycle regulated in non-transformed cultured cells [49]. It is suggested on the basis of these results that HiNFD may be a primary target of neoplastic transformation, and that similar results may pertain in the case of other histone gene transcriptional regulators such as OTF1. This is an interesting idea, although, the data supporting the conclusions of these two studies are not yet convincing. In no case were extracts which have lost HiNFD ~ inding adequately characterized. Specifically, no control DNA probe which binds a non-cell cycle regulated transcription factor was used to normalize for general loss of activity in these extracts. Without such a control, no definitive conclusions concerning the status of HiNFD binding activity in different conditions of growth or differentiation can be drawn. Furthermore, since transcriptional regulation of histone H4 genes occurs in both transformed and normal cell lines, one must conclude that the reported change in HiNFD DNA binding properties in transformed cells had little or no functional consequence for histone gene regulation.

IlL A model for histone gene transcriptional control during S phase It is evident from the experimental data discussed above that transcriptional control of mammalian and avian histone genes during the cell cycle involves the

G I Phase

activation of distinct subtype specific transcription factors upon entry into S phase. This implies the existence of a pleiotropic regulatory mechanism which employs these different factors as substrates, and which may have a broad role in the activation of trans-factors controlling many aspects of S phase specifiL macromolecular synthesis (see Fig. 3). The observed changes in posttranslational modification of OTF1 as cells progress through the cell cycle suggest that the mechanisms regulating the activity of these factors involve modification of preexisting factors by phosphorylation or dephosphorylation. This is particularly evident in mitotic cells, where qualitatively distinct phosphopeptides are easily apparent. One interesting possibility is that OTF1 is precisely regulated at all times in the cell cycle by posttranslational modification. Furthermore, it can be anticipated from the DNA binding studies of OTF1 in serum starved cells [35] and from the developmental regulation of octl DNA binding in Xenopus [38] that additional regulation is operant upon OTF1. Finally, it is probable that the other histone gene cell cycle regulatory proteins (and other as yet unidentified S phase specific trans-factors) are regulated by the same mechanisms as OTFI. The fact that the AC box factor, H1TF2 and, perhaps, HiNFD all appear to exhibit increased DNA binding upon entry into S phase is not seen as inconsistent with our knowledge of properties of OTF1. Rather, in this view it is proposed that analogous modifications of these proteins occur upon progression through the cell cycle, but that the downstream effects of these modifications are mechanistically different. It must be noted that little specific information is available concerning the functional consequences of changes in OTF1 phosphorylation and that essentially no detailed in vivo data is yet available concerning the other histone gene cell cycle proteins. Although in general outline the regulatory scheme presented in Fig. 3 seems quite probable, the specific

S Phase

~R

i-~

H2B

---~ RI--,.R 2 - ~ R n

T K D H F R DNA r e p cat on....~?

Fig. 3 Modelfor transcriptionalcontrolof histonegeneexpressionduringthe cell cycle(see Ref. 17).

335 enzymes which mediate the proposed changes in during the cell cycle have not yet been identified. In spite of this, reasonable guesses at their identity can be made on the basis of the observed changes in OTF1 phosphorylation upon transit through the cell cycle and precedent upon from the literature. In particular, analysis of SV40 T antigen phosphorylation provides a striking paradigm for consideration of these results. Thus, it has recently been demonstrated that the phosphorylation state of T antigen is directly responsible for its functional activities in the initiation of viral DNA synthesis and that changes in T antigen phosphorylation are effected through at least two cell cycle regulated enzymes [50,51]. The original observation that SV40 DNA synthesis is significantly more active in extracts from S phase cells than it is in similar extracts from G1 cells [52] resulted in the purification of an S phase factor responsible for this difference [50]. Sequence analysis of the purified protein revealed it to be protein phosphatase 2A, which allowed the direct demonstration that treatment of T antigen with this phosphatase results in stimulation of its activity in the initiation of viral DNA synthesis. Further analysis established that PP2A is inactive in the G1 extracts, but very active in S phase extracts, providing an explanation for the cell cycle specificity of SV40 DNA synthesis in vitro [50]. From these data it became clear that removal of specific inhibitory phosphate modifications must occur to achieve maximal T antigen activity for initiation of DNA synthesis. On the other hand, comparison of the activity of recombinant, completely unphosphorylated T antigen prepared in Escherichia coil with that produced in eucaryotic cells demonstrated that the unmodified enzyme is of very low specific activity in in vitro DNA synthesis initiation assays. Further analysis showed that activation of the E. coli produced T antigen could be achieved by in vitro phosphorylation at Thr-124 with p34 CDC2 kinase [51 ]. These two studies established that T antigen activity is dependent both upon removal of inhibiting phosphates at the G 1 / S phase border by protein phosphatase 2A [50] and phosphorylation of Thr-124 by CDC2 kinase [51]. It seems possible that one of the normal cellular substrates for these enzymes is octl, and that at least some of its functional properties might be regulated by these enzymes. IV. Posttranscriptional control of histone mRNA abundance As outlined in the introduction to this review, it is clear that histone mRNA abundance is regulated both by transcriptional and posttranscriptional mechanisms. Two phenomena of particular interest regarding the control of histone mRNA are the dynamic close coupling of histone mRNA concentrations and DNA synthesis, and the phenomenon of dosage compensa-

tion. Although this discussion will focus on the first of these issues, the phenomenon of histone mRNA dosage compensation has been established for both mammalian [7] and yeast histone mRNAs [53]. in flae case of mammalian histone mRNAs, introduction of high numbers of histone H4 genes into cells resulted in at least a 10-fold increase in total H4 transcription without a corresponding increase in total histone H4 mRNA. In this case, therefore, the vast majority of histone H4 mRNA transcripts produced did not mature into histone mRNA, although the accumulation of other histone mRNAs remained normal. If the posttranscriptional mechanisms controlling histone mRNAs during the cell cycle are related to those regulating dosage compensation, one can expect that their capacity for regulation far exceeds that required in normal cells and that at least some components of these mechanisms may be subtype specific. 1V-A. Histone m R N A sequences im,oh~ed in posttranscrtptional control

A great deal of effi rt has been expended to assess which sequences within historic mRNA contribute specifically to its regulation during the cell cycle. Two recent reviews [5,61 have appeared which thoroughly discuss these studies. Although they do not definitively preclude a role for any sequence in the mRNA in these posttranscriptional events, they do convincingly demonstrate that the 3' terminal stem loop structure of mammalian histone mRNA is involved in cell cycle control. Two types of evidence support this conclusion. First, it is quite clear that histone mRNAs that are polyadenylated, whether or not they contain the normal histone stem loop sequences at an internal position, can not be properly cell cycle regulated in mammalian cells [5]. Second, fusion of very small elements containing the histone 3' terminal stem loop to heterologous mRNAs results both in correct processing, generation of a histone like 3' terminus, and in cell cycle regulation. For example, fusion of 80 bp of a mouse histone 3' terminus to heterologous mRNAs could result in parallel accumulation of the fusion mRNA with endogenous histone mRNAs after release of 21-Tb cells from G1 arrest [54]. Similarly, fusion of 30 bp surrounding the 3' terminus of a mouse histone mRNA to the human alpha globin gene resulted in rapid degradation of the fusion transcript when DNA synthesis was inhibited with hydroxyurea [55]. Although the provisional conclusion that the 3' stem loop is sufficient for posttranscriptional control of histone mRNA can be reached from these studies, it is important to note that neither study examined the accumulation of these transcripts in the unperturbed cell cycle. It would be particularly useful, for instance, to analyze the kinetics of accumulation and decay of these constructs in cells synchronized by nonintrusive

336 methods such as centrifugal elutriation or mitotic shakeoff to determine whether the 3' sequences are truly sufficient for normal regulation. The possibility that the conclusions reached in the mammalian studies have been oversimplified is supported by recent studies of sequences controlling histone mRNA accumulation in S. ceremsiae [56]. In contrast to mammalian hiztone mRNAs, yeast histone mRNAs do not contain a conserved 3' terminal stem loop structure but are polyadenylated. Analysis of a series of fusion constn~cts with varying contributions from the HTB1 gene demonstrated that some aspects of cell cycle specific accumulation from a constitutively transcribed promoter can be achieved with an approx. 120 bp sequence centered about the translation stop codon. Since this fusion gene terminates normally and is properly processed, it is suggested that this sequence acts by altering the half life of yeast histone mRNAs. Although normal cell cycle regulatic9 of the fusion transcript was not observed, the involvement of sequences within the body of the mRNA can apparently influence the timing of accumulation of the fusion transcript following release from alpha factor arrest in GI. These results may indicate, as the authors suggest, that posttranscriptional control of yeast and mammalian histone mRNAs is achieved through different mechanisms. Alternatively, it seems possible that these studies are reflecting different aspects of a complex system for histone mRNA posttranscriptional regulation.

IV-B. Processing of the histone 3' terminus and the cell cycle Histone mRNAs in higher eucaryotes are generated by endonucleCytic cleavage of a large primary transcript immediately 3' to the conserved stem loop. Analysis of this reaction for both sea urchin [57,58] and mammalian [59,69] histone transcripts has led to a detailed understanding of the sequences controlling this processing event, and identification of three activities which are required in this reaction. Analysis of sequences required for correct processing of a sea urchin histone H3 mRNA first established that both the conserved stem loop structure and a purine rich sequence slightly 3' to the mature mRNA terminus are required for correct processing [57]. This reaction occurred via an endonucleolytic cleavage involving a novel U7 snRNP, whose activity required proper base pairing between a small sequence at the 5' end of U7 RNA and the purine rich consensus downstream from the mature 3' terminus of the mRNA [58]. Subsequent studies of mammalian histone mRNA processing in extracts from cultured cells confirmed that both the stem loop and the purine rich spacer element are required for efficient processing in this system [59,60]. However. these studies revealed that the con-

served stem loop is not absolutely required in the processing reaction, leading to the suggestion that it may be involved in other posttranscriptional regulatory events [60]. This possibility is supported by the observation that translation termination at or near the normal translation stop codon is required for proper regulation of a human H4 mRNA during the cell cycle [7]. Since translation of histone mRNA occurs in the cytoplasm, it was inferred in this study that access to 3' stem loop in the cytoplasm is important for a cytoplasmic event involved in cell cycle regulation. Taken together, these results lead to the speculation that the 3' stem loop at the histone mRNA terminus may be involved both in nuclear processing of the histone gene primary transcript and in control of cytoplasmic histone mRNA stability. At least three trans-acting factors have been detected which are important for processing at the histone 3' terminus. Extensive evidence has documented the importance of the U7 snRNP in the processing reaction, and the U7 snRNP has been cloned from several higher eucaryotes [61]. As mentioned above, interaction of the U7 snRNP with the primary transcript is achieved through base paring with the purine rich consensus element 3' to the mature histone mRNA terminus [58]. A second factor(s) interacting with the conserved histone mRNA stem loop structure has been reported in two separate studies [60,63]. Although the identity of this factor(s) has not been established, it is distinct from U7 snRNA and can contribute greatly to the efficiency of the in vitro processing reaction. A third 'heat-labile' activity has also been implicated in histone Y terminal processing reactions [59]. Thus, brief heat treatment of extracts from cultured cells destroys the processing activity of the extract. Cross complementation experiments have shown that the heat inactivated extracts can be complemented by a 'heat-labile' component which is distinct from the U7 snRNP [63]. Its properties are also different than those of the 3' stem loop binding activities noted above, suggesting that at least three different trans-acting factors participate in histone mRNA processing. Although the proteins comprising these three activities have not yet been purified, a rather sophisticated understanding of the histone 3' processing reaction has been obtained through these studies. Several studies have implicated 3' processing as an important component of histone mRNA regulation upon entry into or exit from the cell cycle [6]. Arrest of the temperature sensitive mouse mastocytoma cell line in G1 results in increased accumulation of histone mRNA precursors due to inefficient 3' terminal processing of the primary transt:lipts [59]. Extracts prepared from G1 arrested cell lines are less efficient than extracts from growing cells for in vitro processing of histone mRNAs, uuc to very low levels of the heat-labile factor discussed above [59]. Studies of histone 3' processing upon release

337 of 10TI/2 cells from serum arrest support the conclusion that processing of the histone primary transcripts is deficient in arrested cell populations [63]. In addition, this study provided quite convincing evidence that failure of these extracts to process the histone 3' end is due to occlusion of the 5' terminus of U7 snRNA, resulting in failure to properly execute its function in mRNA maturation. A strong argument for involvement of the heat-labile factor in accessibility of the U7 5' terminus was also presented. From these and other studies, it seems quite clear that histonc 3' processing is subject to regulation during the transition from cell cycle arrest to active cell growth. Although a role for 3' processing could be envisaged for regulation of histone mRNA abundance in actively cycling cells, no direct evidence supporting this idea has yet been obtained. Rather, it has been suggested [6] that this process is most likely to contribute to regulation of histone mRNA abundance under the relatively static conditions of growth arrest rather than the dynamic control of historic mRNA concentration that has been documented to occur in cycling cell populations. Definitive evidence in this regard will require extensively controlled measurements of histone mRNA processing in extracts from centrifugally elutriated cycling cell populations, or purification, characterization and examination of the components involved in the processing reaction as a function of position in the cell cycle.

V. The regulation of histone mRNA stability during the cell cyde

nonspecific 3' exonuclease has been established which mimics some aspects of histone mRNA turnover in vivo [66]. Addition of free histones to this extract resuhed in accelerated decay of histone mRNA [67], supporting the notion of feedback control. Although the appeal for this model of the regulation of histone mRNA stability is very strong, the evidence supporting it is not yet definitive. For example, although it seems clear that the 3' stem loop is somehow involved in determining the halflife of histone mRNA, it has not yet been established that this element is sufficient for regulation of histone mRNA half-life during the cell cycle. Such a demonstration would require detailed mutagenesis of the mI~NA without interruption of the translation reading frame, since a variety of relatively crude experiments have implicated translation as an important factor in determining histone mRNA half-life. One might, for example, mutate the wobble positions of small groups of codons to assess their ir:fluence on histone mRNA regulation in vi,,o. This would be particularly interesting in the 3' half of the histonc mRNA open reading frames, since the second and third positions of many codons in this region are highly conserved [12]. Alternatively, biochemical dissection of the in vitro system for histone mRNA might eventually lead to identification of factors which are rate limiting for turnover at different points in the cell cycle. Characterization of these factors as cells progress though the cycle could then lead to definitive identification of the regulatory mechanism for controlling histone mRNA stability. VI. Concluding remarks

One of the most impressive facts concerning the regulation of histone mRNA abundance is the very tight coupling between historic mRNA concentration and DNA synthesis. Early studies in this field first documented the extremely rapid degradation of histone mRNA when S phase cells are treated with inhibitors of D N A synthesis [64], leading to the proposal that histone mRNAs might be autogenously regulated [65]. The simplest hypothesis stated that in the absence of DNA synthesis, newly synthesized histones could not be titrated onto chromosomal DNA. These free histones would then feed-back into the mechanisms regulating histone mRNA stability, causing its rapid degradation. The rapid degradation of histone mRNA following inhibition of DNA synthesis has been reproduced in a variety of systems using several different agents to inhibit DNA replication. Direct measurements of histone mRNA stability under these conditions suggests that its half-life decreases several fold from that measured at the peak of S phase in untreated cells [4]. The original model of autogenous control of histone mRNA degradation has received support from recent studies of its degradation in vitro [66,67]. Thus, an in vitro system which can degrade histone mRNA via a

The studies discussed in this brief review focus upon specific issues pertinent to the regulation of histone gene expression during the cell cycle. Ideas concerning the molecular mechanisms which participate in this regulation are being formulated, and the tools to assess them are in some cases at hand. It seems probable that a mechanistic description of some of these regulatory events will emerge in the near future. It is appropriate, then, to try to understand the general biological issues which have arisen from our efforts to dissect this exceedingly complex system. Perhaps the most significant subject for the present discussion is the scope of the regulatory mechanisms revealed in studies of histone gene expression. While it seems likely that certain aspects of histone genc regulation are entirely specific (e.g., dosage compensation), one might easily argue that the mechanisms regulating histone gene expression can also provide fundamental insight into issues of cell cycle progression and growth control. This derives from the simple fact that activation of histone gene expression occurs specifically during S phase and must, therefore, be directly responsive to biochemical cues which change as cells transit through

338 lhe cell cycle. To illustrate this point, it is useful to consider the implications of the model which has arisen to describe transcriptional control of histone genes during S phase (Fig. 3). For example, the existence of a pk;c:rJpic mechanism which can activate at least four distinct transcription factors for histone gene expression up,)n entry into S phase immediately raises the question (,~ sub~trat6 specificity of this mechanism. ~A~h ilo !! !s certainly possible that this mechamsm is present exclusively to control histone synthes,s, it seems likely that it may be involved in activating other trans-acting factors with S phase specific functions. One possibility in this regard con_cerns the contro! of chromosomal DNA synthesis: is this regulatory mechanism also acting to control DNA replication through activation of replication initiation proteins? Obviously, as the molecular details of S phase specific histone transcription emerge it will be possible to test this idea by similar analysis of putative DNA replication initiation factors [68]. A second issue of general importance concerns the role of the activated S phase forms ol the cell cycle regulated transcription factors: is their function really restricted to production of histones? The observations that OTFI is clearly participating in other (presumably) non-cell cycle regulated transcription events [34], and that it can stimulate adenovirus DNA replication in vitro [27] quite clearly presents the possibility that it may also participate in chromosomal DNA synthesis. In this case, it is not the substratc specificity of the putative pleiotropic regulatory mechanism which is broadened to include a new function, but the versatility of its identified substrates in participating in more than one S phase specific event which generalizes the importance of these mechanisms. Finally, if the correlation between different forms of these factors and functional specificity during S phase can be established, one wonders whether the non-S phase species of these factors also have specific roles in the cell cycle. This raises the general issue of cell cycle regulated transcription and the number of factors required to achieve a complex program of transcriptional regulation during the cell cycle, in the extreme, one might imagine that a ,'cry small number of distinct transcription factors, if specihcally modified as a function of cell cycle phase, could control gene expression at all points during transit through the division cycle. Thus, at the intersection between detailed analysis of these transcription factors and known biochemical mechanisms controlling cell cycle progression may stand important signposts for further biochemical dissection of the cell cycle. In closing, I would simply add that this review is necessarily prejudiced by my own experimental emphasis on histone gene transcriptional control. 1 fully expect that further delineation of the posttranscriptionai mechanisms regulating histone mRNA accumulation will re-

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The regulation of histone gene expression during the cell cycle.

327 Bi, :hirnwa et Btophv.wca A eta, 1088 ( 1991 ) 327- 339 .~5 1 ~gt Elsevier Science Publishers B.V. 0167-4781/91/$03.50 A D.gNIS O167478191001006...
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