histone modification and regulation of chromatin function

ISSN 1022-7954, Russian Journal of Genetics, 2006, Vol. 42, No. 9, pp. 970–984. © Pleiades Publishing, Inc., 2006.Original Russian Text © D.E. Koryakov, 2006, published in Genetika, 2006, Vol. 42, No. 9, pp. 1170–1185.

970

NUCLEOSOME STRUCTURE

Almost no free DNA occurs in eukaryotic cellnuclei. DNA is associated with many proteins to form acomplex known as chromatin. The association of DNAwith proteins is not random, but rather shows a stronglyhierarchic multilevel organization wherein nucleosomescorrespond to the first level. Nucleosomes are repetitiveunits that each represent a protein globule with DNAwrapping round it by 1.75 turns [1–3] (Fig. 1). A globuleincludes histones of five types: H1, H2A, H2B, H3, andH4, which are all enriched in basic amino acid residues,lysine and arginine. H2A, H2B, H3, and H4 moleculesform a wedge-shaped core octamer: its narrow part isformed by an (H3–H4)

2

tetramer, and the wide partconsists of two H2A–H2B dimers [4–6]. The C-termi-nal regions of the octamer histones are tightly folded,while the flexible N-terminal regions, also known asN tails, are unfolded and freely radiate outwards [7, 8].One molecule of histone H1 binds to the outer surfaceof the nucleosome in the region of the (H3–H4)

2

tet-ramer, thereby fixing DNA on it [9–13]. Histone H1 hasa globular central region of approximately 80 aminoacid residues and free C and N ends [14]. In bird andreptilian erythrocytes, histone H1 is replaced by itsvariant known as H5 in inactive chromatin [15]. TheDNA region corresponding to one nucleosome varies insize, reaching 200 bp [16, 17]. Of these, 146 bp aredirectly associated with the histone octamer, and theother several tens of base pairs link two neighbornucleosomes [5, 13, 18, 19].

The histone sequences are highly conserved. Theearliest sequencing data showed that histone H4 differsonly in two residues between calf and pea [20, 21]. Thehistone sequences are now known for many organisms,from protozoa to humans [22]. Sequence comparisonsdemonstrated that histones H3 and H4 are conserved to

the greatest extent, while histones H2A and H2B areleast conserved [23].

A detailed study of the sequences showed that his-tones of every type but H4 are heterogeneous in cells ofone organism, forming a family. Each family includes amajor type and minor fractions known as “histone vari-ants.” Different organisms possess up to four variants ofhistone H3, approximately eight variants of histoneH2A, up to seven variants of histone H1, and at leastthree variants of histone H2B. Most, if not all, variantsare associated with a certain process, e.g., transcriptionor X-chromosome inactivation [24–27].

MOLECULAR MARKS

Every process occurring in chromatin is a chain ofenzymatic reactions and essentially concerns transmis-sion, protection, or realization of genetic information.Such processes can be grouped by stability and period-

Histone Modification and Regulation of Chromatin Function

D. E. Koryakov

Institute of Cytology and Genetics, Russian Academy of Sciences, Novosibirsk, 630090 Russia; fax: (383) 330-16-65; e-mail: [email protected]

Department of Cytology and Genetics, Novosibirsk State University, Novosibirsk, 630090 Russia

Received March 2, 2006

Abstract

—Nucleosomes play two main roles, acting as basal units in DNA compaction and coordinating mostprocesses in chromosomes. The coordination is due to modification of histones, proteins forming nucleosomes.The review briefly describes the nucleosome structure and major modifications of histones and considers therole of such modifications in transcriptional suppression and activation.

DOI:

10.1134/S1022795406090043

THEORETICAL PAPERS AND REVIEWS

H1

DNA

N tails

Histoneoctamer

2

×

(H2A–H2B–H3–H4)

Fig. 1.

Organization of an individual nucleosome. Differenthistones are differently shadowed. See text for comments.

RUSSIAN JOURNAL OF GENETICS

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HISTONE MODIFICATION AND REGULATION OF CHROMATIN FUNCTION 971

icity. For instance, the heterochromatin state can bemaintained stable through many cell generations, whileDNA replication in the cell cycle is strongly periodical.The timing of various processes and the temporal andspatial coordination of different processes take advan-tage of molecular marks. In other words, to trigger reac-tion B, a system must detect a mark indicating that reac-tion A is complete. Another problem is that free DNAis necessary for most processes taking place in chroma-tin, while nucleosomal folding seems at first glance tohinder such processes. Yet it is actually nucleosomesthat ensure coordinate functions of chromatin, becausehistones carry the above molecular marks. Acetylationand methylation of some residues in histones wereobserved long before the spatial structure of the nucleo-some was resolved [28–30]. Modification of these andother types provides molecular marks, which can beclassified as genetic and not epigenetic. The formergroup includes stable marks that are not associated withDNA nucleotide sequence, are inherited in successivegenerations, and convey information about a process.Other marks serve to temporally maintain a particularstate of chromatin.

Modification involves mostly free N tails, while theglobular and C-terminal regions of histones are modi-fied to a far lower extent. The best-studied posttransla-tional modifications of amino acid residues are acetyla-tion of lysine, methylation of lysine and arginine, phos-phorylation of serine and threonine, and ubiquitylationof lysine (Fig. 2). Note that such modifications are post-translational indeed; i.e., certain groups are added aftersynthesis of a histone molecule. This effect was demon-strated in experiments with a protein synthesis inhibi-tor: added into a system in vitro, the inhibitor sup-pressed translation but not acetylation and methylation

of amino acid residues in histone molecules synthe-sized before [29].

How do histone modifications affect the organiza-tion and function of chromatin? Two variants are possi-ble. For instance, addition of acetyl groups neutralizesthe positive charge of a histone molecule, while addi-tion of phosphate groups increases the negative charge.Such modifications change the conformation of nucleo-somes and the accessibility of DNA for various proteins[31–33]. According to another hypothesis, the key roleis played by a particular combination of modificationsin a nucleosome rather than by the net charge of a his-tone molecule. Occurring in a given nucleosome, sucha combination “codes” for a particular process. Thecoding mechanism is based on the assumption thatmodified residues selectively bind with certain pro-teins, which trigger a particular chain of reactions,thereby deciphering the histone code. In 2000 and2001, Strahl (United States), Allis (United States), andJenuwein (Austria) [34, 35] formulated this histonecode theory, which is rapidly developing now. Interestin this theory can be illustrated by the fact that the paper[35] was cited more than one thousand times fromAugust 2001 to December 2005. Finally, it is possiblethat the two mechanisms do not exclude each other,functioning in parallel; i.e., both the combination ofmodifications and the net charge of a chromatin regionare important.

METHYLATION

It is clear that stable histone marks are necessary forlong-term processes in chromatin, while short-term andperiodical processes require marks that are easy to setand remove. It was believed for a long time that meth-

Me Me MeMe MeAcPP Ac Ac PMeMe Me Me

Ac MeAcAcAcMe

Ac Ac AcP Ub

UbAcAcAcAc P

120201514125

1 5 9 13 119

3 5 8 12 16 20

2 4 8 9 10 14 17 18 23 26 27 28 36 79

Ac

H3

H4

H2A

H2B

Fig. 2.

Major modifications of amino acid residues in the human core histones. Residues are numbered starting from the N terminus.Modifications: Me, methylation; Ac, acetylation; P, phosphorylation; and Ub, ubiquitylation.

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ylation is stable and that such marks can be removedonly together with the whole histone molecule,although the possibility of enzymatic demethylationwas already known [36]. The concept of methylationstability arose because the attempts to isolate histonedemethylases failed; yet the situation has changedrecently [37].

Today, methylation is known in various organismsfor 17 lysine residues, which each can bear one to threemethyl groups, and for 7 arginine residues, each bear-ing one or two groups [34, 38–45] (Fig. 2). Modifica-tion of these residues plays a role in the formation ofheterochromatin, DNA repair, and transcription regula-tion; the same residue with different number of methylgroups may have different biological functions. Methy-lation is driven by numerous lysine and arginine histonemethyltransferases (HMTs). Most lysine HMTs pos-sess a catalytical SET domain and are divided into fourfamilies (SUV39, SET1, SET2, and RIZ), which differin the position of the SET domain, the substrate speci-ficity, and the presence of other domains [46–48]. Thename of the SET domain originates from the names of

Drosophila

proteins wherein it has been identified(Su(var)3-9, E(z), and Trx). Only a few enzymes meth-ylating H3K79 lack the SET domain [49].

The terminal nitrogen atoms of the side chain ofarginine differ, one belonging to the amino group andthe other, to the imino group. Thus, a dimethylated argi-nine residue can have both methyl groups at the amino-group nitrogen (asymmetrical methylation) or onemethyl group at each of the two different nitrogens(symmetrical methylation). Arginine HMTs are dividedinto two classes. Class I enzymes catalyze asymmetri-cal methylation, whereas class II enzymes are responsi-ble for symmetrical methylation [40, 50]. In both cases,S-adenosyl-L-methionine is utilized as a donor of themethyl group [51]. This compound is a universal donorfor both DNA- and protein-specific methyltransferases.Accordingly, all these enzymes contain a conserved S-adenosyl-L-methionine-binding motif regardless oftheir substrate specificity [52].

The spatial structure of the SET domain was studiedin detail for human SET7/9,

Drosophila

SET8,

Neuro-spora crassa

DIM-5,

Schizosaccharomyces pombe

Clr4, and pea LSMT (for review, see [53, 54]). The SETdomain contains two conserved regions, SET-N andSET-C, and intermediate region SET-I, which is con-served to a lesser extent [54]. The N-flanking sequenceof the domain is important for its stability, while theC-flanking region acts as a binding site for S-adenosyl-L-methionine [53].

Methyl groups are removed by histone demethy-lases (HDMs). The first HDM was recently identified inyeast

S. pombe

and designated as LSD1. This enzymedemethylates H3K4 via oxidation to yield formalde-hyde [55, 56]. Yeast

Saccharomyces cerevisiae

lacksLSD1 homologs, but has JHMD1, another HDM thatspecifically demethylates H3K36. This process is cata-

lyzed by the JmjC domain and utilizes another chemicalreaction, yielding formaldehyde and succinate [57, 58].Homologs of these demethylases were found in variousorganisms, including humans. Arginine demethylationis still poorly understood. It is known only that PAD4converts nonmodified or monomethylated arginine ofhistones H3 and H4 into citrulline via deimination[59, 60].

It is noteworthy that the enzymes known to add orremove the methyl group considerably differ in num-ber. There are 73 genes coding for putative HMTs withthe SET domain in the human genome, 41 in the

Droso-phila

genome, and up to 37 in the nematode

Cae-norhabditis elegans

genome [48]. At the same time, nomore than ten HDMs homologous to LSD1 are encodedin mammalian genomes [37]. Note, however, that pro-teins presumably possessing the JmjC domain are farmore numerous: their number reaches 52 in humans.Yet reliable data are available for only a few demethy-lases, which poses several questions. For instance, aremethylated lysine residues are all capable of demethy-lation? If so, how their demethylation is achieved sinceHDMs are few? Which factors determine the site spec-ificity of demethylation? At least the last question canbe answered. There is evidence that the specificity ofLSD1 is affected by cofactors: LSD1 demethylatesH3K4 when bound with CoREST and H3K9 whenbound with the androgen receptor [61–63].

Another feature of demethylation is also of particu-lar interest. The lysine-specific enzymes are active onlywith di- and monomethylated residues. Trimethylatedresidues are not affected by known HDMs [56, 58]. It ispossible that one or two methyl groups modifying oneresidue mark relatively stable but still reversible pro-cesses, while three methyl groups are marks of irrevers-ible processes.

It is essential for binding with methylated lysine thata protein deciphering the histone code has specificdomains, e.g., chromodomain or Tudor [64–67]. Thefirst identified domain was the chromodomain, whichconsists of approximately 50 residues forming three

β

-sheets opposite to an

α

-helix [68]. A key role in theresulting structure is played by approximately tenhydrophobic residues, which bind the side chain oflysine. To recognize the methyl group, the chromo-domain utilizes three perpendicular aromatic rings,which form a pocket cell [65].

ACETYLATION

The total number of acetylation sites in histones is13–16 according to different estimates [44, 69–72](Fig. 2). Unlike in the case of methylation, only oneacetyl group can be added to a lysine residue. Suchmolecular marks are highly labile, which is due tonumerous histone acetyltransferases (HATs) and his-tone deacetylases (HDACs). Ample evidence accumu-lated to date implicates histone acetylation in transcrip-


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tion regulation, dosage compensation, the cell cycle,and nucleosome assembly.

All HATs are divided into two large classes, depend-ing on the cell compartment where they function. TypeB enzymes function in the cytoplasm, while type AHATs are nuclear. In addition, several families andsuperfamilies of HATs are recognized by the presenceof conserved domains and association with certain pro-tein complexes (GNAT, MYST, p300/CBP, nuclearreceptor coactivators, TAFII250, and TFIIIC) [69, 70].All HATs have homologous catalytic domains. Thespatial structure and the mechanism of action of the cat-alytic domain were studied in detail for PCAF andGCN5 of various organisms. The domain contains sev-eral motifs. The greatest conservation is characteristicof motif A (R/G–x–x–G–x–G/A), which is involved inrecognizing and binding Ac-CoA, which serves as adonor of the acetyl group [73–78].

HDACs are divided into four classes based on theirhomology and nuclear or cytoplasmic localization[79–83]. Enzymes of classes I, II, and III are respec-tively homologous to

S. cerevisiae

RPD3, HDA1, andSir2. Only class III enzymes utilize NAD

+

as a cofactor[84, 85]. HDAC11 is close to class I enzymes, but isisolated in an individual class (IV) because of the lowhomology [83, 86]. Class I and II enzymes possess a cata-lytic domain that consists of approximately 390 aminoacid residues and includes Zn

2+

as an essential compo-nent [87]. In vivo, HDACs are active only in complexwith cofactors [79].

The bromodomain is necessary for recognizing acety-lated lysine in histones and other proteins [88–90]. Thisdomain is approximately 110 residues in size and con-tains four long and one short

α

-helices. About tenamino acid residues of the domain are conserved; theseresidues form a hydrophobic pocket for the binding ofthe side chain of lysine and a charged region within thepocket for hydrogen bonding with the acetyl group[91, 92]. Other residues of the domain determine itsgeneral configuration and specific binding with the sub-strate. In addition, an important role in specificity isplayed by the context of acetylated lysine. For instance,positions K + 2 and K + 3 are crucial for the binding ofthe bromodomain of

S. cerevisiae

GCN5 with acety-lated H4K16 of a histone molecule, while positions K – 1and K + 1 does not affect binding [93]. Some proteinssuch as TAFII250 and Brd4 have double bromo-domains. It is believed that these proteins are capable ofbinding simultaneously with two acetylated lysines(K5/K12 or K8/K16) in histone H4 [94, 95].

PHOSPHORYLATION

Phosphorylation is a labile modification and isknown for all histones (Fig. 2). Phosphorylation isinvolved in two structurally opposite processes: decon-densation of chromatin upon transcription activationand condensation of chromosomes during cell division

or apoptosis [96–98]. A necessary balance betweenphosphorylation and dephosphorylation is maintainedby kinases and phosphatases. Different processesinvolve different sets of enzymes. For instance phos-phorylation of histone H3 during the cell cycle is regu-lated by kinases Ipl1/Aurora and phosphatasesGlc7/PP1 [99–101]. Kinases RSK2, MSK1, and MSK2transfer phosphate groups to histone H3 to activatetranscription [102–104]. The enzyme phosphorylatingH3S10 upon heat shock in

Drosophila

is still unknown,and JIL-1 is regarded as a possible candidate [105].PP2A probably acts as phosphatase that removes phos-phate groups from all other sites during this process [106].

UBIQUITYLATION

In addition to small chemical groups, relativelylarge molecules are utilized for modifying histones. Forinstance, lysine residues can be linked with ubiquitin, apolypeptide of 76 amino acid residues [107]. This mod-ification was demonstrated for only a few positions inhistones H2A and H2B. In contrast to the overwhelm-ing majority of other modification positions, the ubiq-uitylation sites are at the C ends of molecules. HistoneH2A can be ubiquitylated at K119, and histone H2B, atK120/K123 [108–110] (Fig. 2). Ubiquitin is added orremoved by ubiquitin ligases and proteases [111].

Thus, the four types of the best-studied covalentmodifications of histones have been considered above.The following sections focus on the role of thesemolecular marks in the fundamentally differing pro-cesses of transcriptional suppression and activation.

TRANSCRIPTIONAL SUPPRESSION (SILENCING)

The common term silencing implies various pro-cesses that lead to heritable epigenetic suppression oftranscription, including the formation of pericentricheterochromatin, dosage compensation in mammals,gene inactivation in yeast

S. cerevisiae

, and regulationof homeotic genes in

Drosophila.

In general, these pro-cesses are characterized at least by the absence of labilemodification (such as acetylation), the presence of sta-ble marks (e.g., methylation of H3K9, H3K27, andH4K20), and DNA methylation. Since a lysine residuecan bear one to three methyl groups, every silent regionhas a specific combination of epigenetic marks. Suchmarks are epigenetic indeed, being inherited throughcell generations.

The main modification characterizing mammalianpericentric heterochromatin is H3K9 trimethylationcatalyzed by Suv39h1 [112]. Trimethylation of H4K20and monomethylation of H3K27 are two other modifi-cations that prevail in these chromosome regions. WhenH3K9 trimethylation is lacking, a trimethylated, ratherthan monomethylated, form of H3K27 accumulatesand H4K20 trimethylation disappears [113, 114].

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Unlike in mammals, the main epigenetic mark of

Drosophila

pericentric heterochromatin is H3K9 dime-thylation catalized by Su(var)3-9, which is homologousto Suv39h1 [115, 116]. Trimethylated H3K9 andH3K27 are few in

Drosophila

heterochromatin, whilemonomethylated and dimethylated H3K27 residues arerelatively abundant [117].

A specific set of epigenetic marks is generated in themammalian X chromosome upon its inactivation by adosage compensation system [118]. Inactivation is anintricate process, and its initiation and maintenancerequire different marks. During initiation, synthesis ofthe

Xist

RNA stimulates trimethylation of H3K27 andmonomethylation of H4K20, but these marks do notlead to genetic inactivation [119–121]. Transcriptionalsilencing results from dimethylation of H3K9 [122–125]. H3K9-specific HMTs functioning in pericentricheterochromatin and in the X chromosome differ andare not interchangeable. The X-chromosomal enzymeis G9a [124–126]. In addition, important features of theinactive X chromosome are DNA methylation [127]and histone hypoacetylation [128].

The process of H3K9 methylation and its conse-quences have been studied in detail in various organ-isms. It was believed until recently that H3K9 is theonly residue whose acetyl group can be replaced bymethyl groups, while other lysine residues can bearonly one of these modifications. In

Drosophila,

acety-lated H3K9 is deacetylated by RPD3, which provides asignal for methylation by Su(var)3-9, which functionsin complex with RPD3 [129] (Figs. 3a–3d). A similarsituation was observed for

S. pombe

: methylation of

H3K9 by Clr4 is preceded by its deacetylation by Clr6[130, 131]. It is possible that

Drosophila

Su(var)3-9and HDAC1 are not the only enzymes involved in theprocess, because Su(var)3-9 is responsible for approxi-mately 80% of dimethylation and, probably, for all100% of trimethylation. The presence of a dimethy-lated form in chromosome 4 and monomethylation areindependent of this HMT, suggesting the presence ofanother H3K9-specific enzyme (or two enzymes) in

Drosophila

[116, 117].

After this, methylated H3K9 is recognized by vari-ous proteins that trigger processes associated withsilencing. For instance, the Pdd1 and Pdd3 proteinsinteract with methylated H3K9 and trigger chromatindiminution in

Tetrahymena

[132]. The interaction withH3K9 has been studied in most detail for heterochro-matin protein 1 (HP1), which, in turn, is capable ofrecruiting many other proteins [65, 130, 133–136]. Forinstance, HP1 binding to H3K9 is essential for therecruitment of H4K20-specific HMT Suv4-20 andH4K20 methylation in mammals and

Drosophila

[114](Figs. 3e–3i). There is ample evidence that HP1 corre-lates with genetic inactivation [137–140]. However, theprocesses involving HP1 are greatly diverse and can beassociated with transcription as well [141–146].

Methylation of H3K9 is necessary for the recruit-ment of DNA methyltransferases. This process is medi-ated by HP1 or other proteins binding to H3K9 [147–155]. An opposite dependence has also been observed[156, 157]. Methylated cytosines occurring in DNAbind with proteins having the methyl-binding domain(MBD). In turn, these proteins recruit HDACs and

HDACRPD3

HMT ?

HMTSu(var)3-9

HMTSET8

HMT ?

HP1

HMTSuv4-20

HP1

H4K20

H4

H4

H4 H3

H3

H3

H3

H3

H3 (a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

Fig. 3.

Processes occurring during the formation of pericentric heterochromatin in

Drosophila.

Filled bars with horizontal lines, thecore regions and N tails of histones H3 and H4. Black squares show one, two, or three methyl groups at H3K9 and H4K20 (c–f, h, i);gray triangles show the acetyl group at H3K9 (a, b). See text for comments.

H3K9


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HMTs for transferring the methyl group to H3K9.Moreover, some HMTs (e.g., ESET and CLLL8) har-bor MBD and, possibly, are capable of binding directlyto DNA [48, 158, 159]. Such a bi-directional interac-tion probably serves for memorization of the histonemodification pattern during DNA replication andassembly of new nucleosomes, thereby playing animportant role in the inheritance of epigenetic marks.

Methylation of H3K27 is involved in another inacti-vation system. As with H3K9-dependent repression,the relevant system is conserved and has many commonfeatures in different organisms such as

Drosopila

andmammals, although some differences are also known[160, 161]. The system involved about two dozens ofproteins, which belong to the Polycomb group (PcG).The PcG proteins form individual interacting com-plexes. Two such complexes, PRC1 and PRC2 (Poly-comb repressive complex) are known in

Drosophila

,and four (PRC1–PRC4), in mammals.

Drosophila

PRC1 includes proteins that recognize specific DNAsequences known as PcG response elements (PREs)and determine the inactivation site. Note that PREshave so far been identified in

Drosophila

but not inmammals. In addition, PRC1 includes the Polycombprotein (PC) in

Drosophila

and its homolog HPC inmammals [162–165]. PCR2 possesses histone methyl-transferase activity due to a specific subunit, which isknown as E(z) in

Drosophila

and EZH2 in humans[166–168]. In addition to PRC2, two other human com-plexes, PRC3 and PRC4, contain EZH2 and, conse-quently, are capable of methylating lysine residues inhistones. The site specificity of the complexes differsand depends mostly on the context of the target lysine.For instance, E(z) contained in

Drosophila

PRC2 meth-ylates mostly H3K27 and, to a lesser extent, H3K9in vitro [167]. These residues belong to the commonmotif ARKS. In vivo, a lack of E(z) affects the propor-tion of methylated H3K27, but not H3K9 [117]. As acomponent of PRC2, human EZH2 methylates bothH3K27 and H1K26, the latter also belonging to theARKS motif.

Drosophila

histone H1 is not methylatedby E(z), which can be explained by the lack of thismotif. As a component of PRC3, EZH2 methylates onlyH3K27 and only in the absence of histone H1 [169].PRC4 contains not only EZH2, but also NAD

+

-depen-dent deacetylase SirT1, and is possibly capable todeacetylate and then methylate H1K26 [169–171].

The exact function has so far been established foronly some components involved in PC-dependentsilencing. To simplify, this process can be reduced toH3K27 methylation by E(z) contained in PRC2. In

Drosophila

, methylation affects nucleosomes that sur-round PREs. Modified H3K27 binds with PRC1through the chromodomain of the PC protein [172,173]. This interaction is necessary for Ring1/ESC, aPCR1 component that has a ubiquitin ligase activityand is capable of modifying H2AK119 [174, 175]. Inaddition, EZH2 contained in PCR2/3 interacts withDNA methyltransferases, which methylate DNA in

PRC-binding sites. This possibly ensures the epigeneticinheritance of PC-dependent repression [176].

The

S. cerevisiae

silencing system is of particularinterest, since it substantially differs from the corre-sponding systems of other organisms. Pericentric het-erochromatin is absent from

S. cerevisiae

; its analogsare mating-type loci, rRNA genes, and telomeres [177].There is no H3K9-specific HMT, H3K9 methylation,and HP1 homologs in

S. cerevisiae

lacks [178]. More-over, H3K27 can be acetylated but not methylated in

S. cerevisiae

, while the situation is opposite in otherorganisms. The

S. cerevisiae

silencing system employsproteins known as silent information regulators (Sir1–Sir4) [179, 180]. Like with the

Drosophila

PcG pro-teins, their binding requires certain DNA sequencesknown as silencers. All four Sir proteins function tosilence the mating-type loci, while telomere silencingdoes not require Sir1 [181]. A lack of Sir3 and Sir4 doesnot affect silencing of the rRNA gene cluster [182].Thus, only Sir2, acting as histone deacetylase, func-tions in all silent regions [183]. Sir2 is a class IIIenzyme, while deacetylases involved in silencing in

Drosophila

and

S. pombe

belong to class I. Sir2deacetylates H4K16, which leads to subsequentdeacetylation of other lysine residues. Deacetylation,rather than methylation, of lysine residues is the mainprerequisite to transcriptional suppression of all silentregions in

S. cerevisiae

as opposed to other organisms.In telomeres and mating-type loci, deacetylated H4binds a complex containing Sir3, which recruits newmolecules of Sir2 and Sir4 and thereby causes a spread-ing of silencing [184, 185].

TRANSCRIPTION

Transcription is a multistep process and includes ini-tiation, elongation, and termination, which are controlledby different protein complexes. The situation is evenmore intricate, since genes differ in the pattern of theirexpression. For instance, housekeeping genes are alwaysactive in all tissues. The heat shock genes are potentiallyactive: they may never function and can be rapidly acti-vated in response to certain environmental factors. Geneslocated in heterochromatin require a specific regulatorysystem, differing from that of euchromatic genes. Thus,the intricate process of transcription requires an intricatesystem of marks, involving acetylation, methylation,phosphorylation, and ubiquitylation. Modificationsshould be intensely changed during transcription, andsuch changes should be initiated anew in every cell gen-eration. Thus, the marks that regulate transcription can-not be regarded as epigenetic. The process has been stud-ied best in

S. cerevisiae

; however, the regulatory modifi-cations are much the same in different organisms onexperimental evidence.

Transcription initiation in yeast

S. cerevisiae

andhuman cells require acetylation of H3K9, H3K14, andhistone H4 and nucleosome remodeling in the promoterand 5'-terminal regions of a gene. Such modifications

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are far fewer in the coding region [186, 187]. Acetyla-tion was effected by acetyltransferase complexes, e.g.,GCN5 and ESA1, the highest number of which was alsoat the promoter region [188, 189]. It is important to notethat the proportion of acetylated nucleosomes is maximalin the 5'-coding region rather than in the promoter. Thisagrees with the fact that nucleosomes are virtually absentfrom the promoters of active genes [187, 190, 191].

The group of immediate-early response genesrequires a special initiation system. These genes lack acertain temporal expression profile and are rapidly acti-vated in response to environmental stimuli such as hor-mones, protein synthesis inhibitors, heat shock, andirradiation. Their activation involves phosphorylationof H3S10. This modification appears early after expo-sure to an external stimulus and is short-lived.

In

S. cerevisiae

and mammals, H3S10 modificationcorrelates with hyperacetylation of the same nucleo-some, suggesting a co-operation of these modifications[192–194]. Two hypotheses have been advanced toexplain the role of phosphorylation in activation. Accord-ing to one hypothesis, phosphorylation is an essential pre-requisite to subsequent acetylation. In

S. cerevisiae

, SNF1kinase functions together with GCN5 phosphorylase onthe

INO1

promoter and phosphorylates H3S10, whichprovides a binding site for GCN5 for subsequent acety-lation of H3K14 [195, 196]. Other data suggest thatacetylation and phosphorylation act independently. Forinstance, activation of immediate-early response genesin cultured mammalian cells is accompanied by H3phosphorylation but does not increase the extent of his-tone acetylation [104, 197]. Heat shock leads to a com-plete redistribution of H3S10 phosphorylation sites onpolytene chromosomes in

Drosophila

larvae. At a nor-mal temperature, this modification is present in allactively transcribed regions. As temperature increases,activation of the heat shock genes is accompanied by denovo phosphorylation of nucleosomes associated withtheir loci, while this modification disappears from allother regions of the genome. These changes are notaccompanied by any changes in the extent of acetyla-tion of H3K14 and H4K8 [198].

The transition from transcription initiation to elon-gation is associated with methylation of H3K4, whichcan bear one to three methyl groups. The distribution ofdi- and monomethylated forms of H3K4 through chro-matin is relatively homogeneous, while a peak of trim-ethylated H3K4 corresponds to the promoter and 5'-ter-minal regions of active genes in

S. cerevisiae,

human,mouse, and chicken cells, clearly distinguishing thesegenes from inactive genes [187, 199–201]. The firstmethyl group is added by HMT homologous to mam-malian Set9 [202]; the second and third groups areadded by an enzyme homologous to yeast Set1 [178,203, 204]. Phosphorylation of RNA polymerase II bythe TFIIH complex is an essential prerequisite to Set1binding to chromatin in

S. cerevisiae

and, consequently,trimethylation of H3K4. This chain of events results in

elongation; trimethylation of H3K4 in the promoterregion persists for a long time, providing a molecularmark of recent transcriptional activity and, possibly,playing an important role in reinitiation of transcription[205]. It cannot be excluded that trimethylation ofH3K4 in the 5' region of a gene is involved in RNA pro-cessing. Set1 contains an RNA-recognizing motif andis associated with a multisubunit complex that containsthe Swd2 protein. In turn, Swd2 is involved in matura-tion of the 3' end of newly synthesized RNA [203].

There is evidence that ubiquitylation is necessaryfor transcriptional activation. In

S. cerevisiae

cells, acti-vation of the

GAL1

and

SUC2

genes is accompanied byubiquitylation of H2BK123 in nucleosomes of the pro-moter regions. This modification is short-lived andserves to recruit the SAGA acetyltransferase complex.The complex contains the Ubp8 protein, whichremoves ubiquitin residues [206]. In addition, ubiquity-lation is associated with methylation of H3K4 andH3K79. Modification of the latter correlates with activetranscription, although its role in the process is stillunclear. Human UbcH6 and hBRE1 ubiquitylateH2BK120, which is essential for methylation of K4 andK79 and expression of some genes. Suppression ofubiquitin-binding proteins exerts an opposite effect[207, 208]. In

S. cerevisiae

, H2BK123 ubiquitylation isimportant for addition of the second and third methylgroups to H3K4 and H3K79, rather than for monome-thylation of these residues [209].

Transcription elongation is accompanied by methy-lation of K36 in the core region of histone H3 in yeast

S. cerevisiae

and chicken cells. Unlike with H3K4, apeak of di- and trimethylated forms of H3K36 is in the3' part of the coding region rather than in the promoterregion of a gene [187, 210]. This modification dependson Set2, which is also detectable only in the codingregions of genes [211, 212]. Like with H3K4, methyla-tion of H3K26 requires phosphorylation of RNA poly-merase II, but at another site. Set2 contains the specificSRI (Set2 Rpb1 interacting) domain, which binds onlywith phosphorylated RNA polymerase [212–215]. Amutation of the SRI domain of Set2 or a lack of phos-phorylation of RNA polymerase blocks the interactionof the two enzymes, prevents methylation of H3K36,and eventually distorts elongation. During elongationin

S. cerevisiae

, methylated H3K36 binds with a com-plex containing RPD3 histone deacetylase. This enzymeremoves acetyl groups from the sequence that hasalready been transcribed, which possibly prevents tran-scription initiation on cryptic promoters located withinthe coding region [216, 217]. Note that, in

S. cerevisiae

,H3K36 methylation is independent of H2B ubiquityla-tion, while methylation of H3K4 and H3K79 is associ-ated with this modification [218].

CONCLUSIONS

Studies with model subjects of various taxonomicgroups have shown that histone modification is a uni-


Vol. 42

No. 9

2006


versal system regulating the function of chromatin. Dif-ferent organisms have common principles of the his-tone code, and homologous enzymes modify the sameresidues in most cases. Yet every organism has its spe-cifics, as is the case with gene silencing in

S. cerevisiae.

Moreover, dinoflagellates (

Dinophyta

) provide anexception to eukaryotic rules. These unicellular organ-isms lack nucleosomes, histones, and their modifica-tions in their common form. The packing of dinoflagel-late chromosomes involves proteins that have nohomologs in other organisms. The histone–DNAweight ratio is approximately 1 : 1 in the eukaryoticnucleus, while histone-like proteins amount to only10% of the DNA weight in dinoflagellates [219, 220].This exception indicates that, universal as it is, the his-tone code is not the only system regulating the functionof chromatin.

As evident from ample data, the histone code isintricate and various modifications are involved in hier-archic interactions known as cross-talk. Some chemicalmodifications always correlate with each other, whilesome others are antagonistic [44, 221]. Moreover, thehistone code is to an extent multivalued. A modificationcharacteristic of heterochromatin can play a role ingene activation in some cases. A modification involvedin transcription can be involved in transcriptional sup-pression under certain conditions. For instance, Ash1(HMT) is capable of methylating simultaneouslyH3K4, H3K9, and H4K20. On genetic evidence, thefunction of the ash1 gene is necessary for activation ofthe Ubx gene in imaginal disks of the third leg pair inDrosophila [222]. This activation requires simulta-neous methylation of the three lysine residues innucleosomes located in the Ubx promoter and a conse-quent recruitment of the Brm transcriptional activator[223]. Thus, the modifications that are usually alterna-tive occur together in this case. Although H3K4 methy-lation is necessary for the transition from transcriptioninitiation to elongation in S. cerevisiae, this modifica-tion causes silencing in the ribosomal gene cluster andtelomeres [178, 224]. Thus, combinations of modifica-tions, rather than individual modifications alone, gov-ern the function of chromatin, and the role of a particu-lar modification depends on its context.

ACKNOWLEDGMENTS

I am grateful to A.A. Gorchakov and T.D. Kolesnikovafor help in searching for literature sources, advice, andfruitful discussion.

This work was supported by the program “Molecu-lar and Cell Biology” of the Presidium of the RussianAcademy of Sciences (project no. 10.1), the Interdisci-plinary Integration Project of the Siberian Division ofthe Russian Academy of Sciences (no. 45), and the Rus-sian Foundation for Basic Research (project no. 06-04-48387a).

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