Nucleosomal packaging of eukaryotic DNA and regulation of transcription
The eukaryotic nucleus harbors genomic DNA, which is tens of thousands of times greater in linear size than the nuclear diameter. Its high condensation is due to DNA packaging in chromatin, and DNA wrapping around nucleosomal globules is a key step in the process. A histone octamer, which forms the...
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irk-123456789-1545802019-06-16T01:32:21Z Nucleosomal packaging of eukaryotic DNA and regulation of transcription Golov, A.K. Razin, S.V. Gavrilov, A.A. Reviews The eukaryotic nucleus harbors genomic DNA, which is tens of thousands of times greater in linear size than the nuclear diameter. Its high condensation is due to DNA packaging in chromatin, and DNA wrapping around nucleosomal globules is a key step in the process. A histone octamer, which forms the nucleosomal globule, interacts with DNA via electrostatic contacts. DNA–histone interactions are rather tight and prevent nucleosomal DNA from being accessed by various enzymes and transcription factors. At the same time, nucleosomes do not prevent transcription and other processes related to the genetic function of DNA. The review considers the structure and diversity of nucleosomes and the central role they play in regulating transcription. Special emphasis is placed on how internucleosomal interactions contribute to genome accessibility to transcription machinery and how nucleosomes are removed from regulatory elements and transcription units in a controlled manner during transcription elongation. Ядра евкаріотних клітин містять геномну ДНК, лінійні розміри якої у десятки тисяч разів перевищують їхній діаметр. Багато в чому такий високий ступінь компактизації забезпечується упаковкою ДНК у хроматин, ключовим етапом якої є намотування ДНК на нуклеосомні глобули. Октамер гістонів, які складають нуклеосомну глобулу, взаємодіє з ДНК за посередництвом електростатичних контактів. ДНК-гістонові взаємодії достатньо міцні і утруднюють доступ до нуклеосомної ДНК багатьох ферментів і транскрипційних факторів. У той же час наявність нуклеосом не перешкоджає проходженню транскрипції та інших процесів, пов’язаних з реалізацією генетичних функцій ДНК. В огляді розглянуто структуру і розмаїття нуклеосом та їхню центральну роль у регуляції транскрипції. Особливу увагу приділено значенню міжнуклеосомних взаємодій у забезпеченні доступності геному для транскрипційної машинерії, а також регульованому видаленню нуклеосом з регуляторних елементів і транскрипційних одиниць в процесі елонгації транскрипції. Ядра эукариотических клеток содержат геномную ДНК, линейные размеры которой в десятки тысяч раз превышают их диаметр. Во многом такая высокая степень компактизации обеспечивается упаковкой ДНК в хроматин, ключевым этапом которой является наматывание ДНК на нуклеосомные глобулы. Октамер гистонов, составляющих нуклеосомную глобулу, взаимодействует с ДНК посредством электростатических контактов. ДНК-гистоновые взаимодействия достаточно прочны и затрудняют доступ к нуклеосомной ДНК многих ферментов и транскрипционных факторов. В то же время наличие нуклеосом не препятствует прохождению транскрипции и других процессов, связанных с реализацией генетических функций ДНК. В настоящем обзоре рассмотрены структура и многообразие нуклеосом и их центральная роль в регуляции транскрипции. Особое внимание уделено значению межнуклеосомных взаимодействий в обеспечении доступности генома для транскрипционной машинерии и регулируемому удалению нуклеосом с регуляторных элементов и транскрипционных единиц в процессе элонгации транскрипции. 2014 Article Nucleosomal packaging of eukaryotic DNA and regulation of transcription / A.K. Golov, S.V. Razin, A.A. Gavrilov // Вiopolymers and Cell. — 2014. — Т. 30, № 6. — С. 413-425. — Бібліогр.: 211 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0008BB http://dspace.nbuv.gov.ua/handle/123456789/154580 577.21 en Вiopolymers and Cell Інститут молекулярної біології і генетики НАН України |
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Reviews Reviews |
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Reviews Reviews Golov, A.K. Razin, S.V. Gavrilov, A.A. Nucleosomal packaging of eukaryotic DNA and regulation of transcription Вiopolymers and Cell |
| description |
The eukaryotic nucleus harbors genomic DNA, which is tens of thousands of times greater in linear size than the nuclear diameter. Its high condensation is due to DNA packaging in chromatin, and DNA wrapping around nucleosomal globules is a key step in the process. A histone octamer, which forms the nucleosomal globule, interacts with DNA via electrostatic contacts. DNA–histone interactions are rather tight and prevent nucleosomal DNA from being accessed by various enzymes and transcription factors. At the same time, nucleosomes do not prevent transcription and other processes related to the genetic function of DNA. The review considers the structure and diversity of nucleosomes and the central role they play in regulating transcription. Special emphasis is placed on how internucleosomal interactions contribute to genome accessibility to transcription machinery and how nucleosomes are removed from regulatory elements and transcription units in a controlled manner during transcription elongation. |
| format |
Article |
| author |
Golov, A.K. Razin, S.V. Gavrilov, A.A. |
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Golov, A.K. Razin, S.V. Gavrilov, A.A. |
| author_sort |
Golov, A.K. |
| title |
Nucleosomal packaging of eukaryotic DNA and regulation of transcription |
| title_short |
Nucleosomal packaging of eukaryotic DNA and regulation of transcription |
| title_full |
Nucleosomal packaging of eukaryotic DNA and regulation of transcription |
| title_fullStr |
Nucleosomal packaging of eukaryotic DNA and regulation of transcription |
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Nucleosomal packaging of eukaryotic DNA and regulation of transcription |
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nucleosomal packaging of eukaryotic dna and regulation of transcription |
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Інститут молекулярної біології і генетики НАН України |
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2014 |
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Reviews |
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http://dspace.nbuv.gov.ua/handle/123456789/154580 |
| citation_txt |
Nucleosomal packaging of eukaryotic DNA and regulation of transcription / A.K. Golov, S.V. Razin, A.A. Gavrilov // Вiopolymers and Cell. — 2014. — Т. 30, № 6. — С. 413-425. — Бібліогр.: 211 назв. — англ. |
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Вiopolymers and Cell |
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REVIEWS
UDC 577.21
Nucleosomal packaging of eukaryotic DNA
and regulation of transcription
A. K. Golov1, S. V. Razin1, 2, A. A. Gavrilov1
1Institute of Gene Biology, Russian Academy of Sciences
34/5, Vavilov Str., Moscow, Russian Federation, 119334
2Faculty of Biology, M. V. Lomonosov Moscow State University
1/12, Vorobyovi gory, Moscow, Russian Federation, 119991
aleksey.a.gavrilov@gmail.com
The eukaryotic nucleus harbors genomic DNA, which is tens of thousands of times greater in linear size than the
nuclear diameter. Its high condensation is due to DNA packaging in chromatin, and DNA wrapping around nuc-
leosomal globules is a key step in the process. A histone octamer, which forms the nucleosomal globule, interacts
with DNA via electrostatic contacts. DNA–histone interactions are rather tight and prevent nucleosomal DNA
from being accessed by various enzymes and transcription factors. At the same time, nucleosomes do not prevent
transcription and other processes related to the genetic function of DNA. The review considers the structure and
diversity of nucleosomes and the central role they play in regulating transcription. Special emphasis is placed on
how internucleosomal interactions contribute to genome accessibility to transcription machinery and how nuc-
leosomes are removed from regulatory elements and transcription units in a controlled manner during trans-
cription elongation.
Keywords: chromatin, histone modifications, nucleosome, transcription.
Introduction. Histones are among the most conserved
eukaryotic proteins [1]. The mere fact points to an extre-
mely important role they play in the eukaryotic cell. For
a long time, studies of histones and chromatin focused
primarily on the structural aspect, elucidating how DNA
is compactly packaged in the nucleus [2]. However, the
role nucleosomes may play in regulating differential ge-
ne expression and other processes related to the geno-
me function came into consideration almost as soon as
nucleosomes were discovered [3]. It is beyond doubt
now that several regulatory mechanisms work at the le-
vel of DNA packaging in chromatin to control various
aspects of genome function, including the so-called
epigenetic memory mechanisms, which play a key role
in establishing the identity of differentiated cells. The
transcription-regulating role of nucleosomes is a main
focus of this review. Special emphasis is placed on how
the nucleosome structure and positioning on DNA are
associated with the regulation of transcription. A limi-
ted number of model loci – such as the beta-globin ge-
nes of vertebrates or PHO5, GAL1-10, and HIS3 of
yeasts – were used for many years to study functional
activity of the genome organized in chromatin. The re-
sults obtained with the model systems were extrapola-
ted to the whole genome. High-throughput sequencing
technology developed in the past decade allowed a num-
ber of methods, such as ChIP-seq, Dnase-seq, and others,
to be used to verify the structural–functional correlations
at the whole genome level. We have tried to involve the-
se new data wherever possible.
First, the structures of the basic nucleosomal partic-
le and 10-nm chromatin fiber, which is composed of
nucleosomes, are briefly considered in the review. Then
we discuss the modern data that indicate a lack of re-
gular interactions between nucleosomal particles in
the eukaryotic nucleus. Emphasis is placed on the spe-
cifics of nucleosome positioning on DNA and prima-
rily on nucleosome-free regions, which usually harbor
413
ISSN 0233–7657. Biopolymers and Cell. 2014. Vol. 30. N 6. P. 413–425 doi: http://dx.doi.org/10.7124/bc.0008BB
� Institute of Molecular Biology and Genetics, NAS of Ukraine, 2014
414
various regulatory elements of the genome. Transcrip-
tion of nucleosomal DNA is also considered. The final
part describes the current views of the modulation of
internucleosomal interactions and its role in regulating
transcription.
Nucleosome fiber is a basic structure of chroma-
tin. The 10-nm nucleosome fiber is the level of DNA
packaging in chromatin that is best understood now [4,
5]. The fiber is a DNA molecule interacting regularly
with protein globules known as the nucleosome cores.
A DNA region of 145–147 bp is wrapped around each
globule. The DNA region forms 1.65 left-handed super-
helical turns. The globule consists of eight core histo-
nes. Having a modular organization, the globule is a
complex of an (H3–H4)2 tetramer and two H2A–H2B
dimers [6]. The structure of a nucleosomal particle (a
core with DNA wrapped around it) was solved to 1.9 �
by X-ray analysis [7]. The histones of the octamer are
organized in a left-handed helix, which sterically mat-
ches the superhelical turns of the wrapping DNA frag-
ment. The histone arrangement along the DNA molecu-
le is as follows: the H2A–H2B dimers contact DNA at
the entry and exit of the nucleosomal particle, while the
(H3–H4)2 tetramer contacts the central part of the DNA
region wrapped around the nucleosomal globule. The
nucleotide sequence-independent interaction of the nuc-
leosome core with DNA is due to ionic, hydrogen, and
hydrophobic bonding of the proteins with the DNA su-
gar–phosphate backbone. Two structural and functio-
nal domains are recognized in the core histones. The do-
mains are a histone tail (~ 20–35 nonstructured N-ter-
minal amino acid residues) and a histone fold (the other
~ 80–100 residues), which consists of three�-helical re-
gions linked by small loops. Two short (10–14 residues
each) helices of the histone fold flank a longer helix,
which consists of 28 residues. Along with additional se-
condary structure elements unique to each of the core
histones, the histone fold ensures the majority of histo-
ne interactions with nucleosomal DNA and other histo-
nes. A DNA region between two neighbor nucleoso-
mes is known as the linker and varies from 10 to 90 bp
among different organisms, different cells, and different
genome regions [8]. Histone H1, which substantially
differs in both size and structure from the core histones,
can bind to the linker at the nucleosome entry–exit si-
tes, thus closing two full superhelical turns. Histone H1
is presumably involved in maintaining the supranucleo-
somal packaging levels [9, 10]. The nucleosome fiber
is a basic structure of eukaryotic chromatin. The only
exceptions are dinoflagellate chromatin [11] and male
gamete chromatin in many eukaryotic groups, including
mammals [12].
A conserved character was emphasized for nucleo-
somal particles over many years. Now it is clear that
nucleosomes are not all identical. Modified nucleoso-
me forms occur along with canonical nucleosomes in
chromatin. To produce these forms, variant histones
are incorporated in nucleosomes and posttranslational
modifications made to histones of the nucleosomal glo-
bule. More than one hundred of posttranslational modi-
fications have been observed in histones to date [13, 14],
of which the best known are acetylation (at lysines),
methylation (at lysines, arginines, and histidines), phos-
phorylation (at serines), poly-ADP-ribosylation (at glu-
tamates), ubiquitination, and SUMOylation (at lysi-
nes). Proline cis–trans isomerization is also possible.
The development of new methods, especially those ba-
sed on mass spectrometry [15], allowed the identifica-
tion of new histone posttranslational modifications, such
as O-glycosylation at serine and threonine [16], formy-
lation and crotonylation at lysine, and hydroxylation at
serine [17].
The main targets of posttranslational modification
occur in the nonstructured N-terminal tail domains of
histones [13, 14], although exceptions are possible; i. e.,
several residues acting as targets for functionally impor-
tant modification are in the globular histone regions [18,
19]. As already mentioned, many variant histones exist
along with the canonical one; they are encoded by sepa-
rate genes and can be incorporated in a nucleosome in
place of their canonical counterparts (via a replication-
independent mechanism, while canonical nucleosomes
are assembled on newly synthesized DNA molecules).
The nucleosomes that incorporate variant histones often
differ from canonical nucleosomes to a substantial ex-
tent and perform special functions, for example modula-
te transcriptional activity [20–23] The variant histones
characterized most comprehensively include CENP-A
(centromeric H3), H3.3, macroH2A, H2A.Bbd, H2A.Z,
H2A.X, and H5 (variant H1) [24].
Lateral internucleosomal interactions and the 30-
nm fiber. It was believed until recently that a nucleoso-
GOLOV A. K. ET AL.
mal thread folds in vivo to produce a regular structure
of 30 nm in diameter, which is known as the 30-nm fi-
ber. In vitro, these structures form in the presence of his-
tone H1 or high concentrations of divalent cations [25,
26]. Two main models were advanced for the nucleoso-
me thread folding in the 30-nm fiber. One suggests that
the 10-nm fiber folds into a solenoid containing 6 nuc-
leosomes per turn (one-start helix) [25]. According to
the other model, a nucleosome thread forms a zigzag
structure (two-start helix) [27–29]. Several other, less
common models were discussed along with the above
ones [30]. While the fine organization of the 30-nm fi-
ber was a matter of dispute, it seemed unquestionable
until recently that 30-nm fibers occur in the eukaryotic
nucleus. As experimental methods improved and the in-
terpretation of experimental findings was refined, the
question arose as to whether 30-nm chromatin fibers ac-
tually exist in vivo in both interphase nuclei and meta-
phase chromosomes [31–34]. A molten polymer model
was proposed on the basis of new findings to describe
the folding of the 10-nm fiber in the interphase nucleus
[31–33]. The model postulates that the 10-nm fiber pro-
duces an irregular dynamic structure via internucleoso-
mal interactions between its distant regions «in trans».
This fold is thought to provide for a more plastic chro-
matin packaging as compared with the 30-nm fiber,
thus eventually facilitating all chromatin-related proces-
ses [31–33]. The molten polymer model allows spatial-
ly close nucleosomes to form the same internucleoso-
mal interactions that were observed for structures like
the 30-nm fiber, but the interactions are not regular in
the molten polymer, arising and breaking down in a sto-
chastic manner. Indeed, one of the key interactions in
the molten polymer is a contact of the N-terminal do-
main of histone H4 with an acidic patch of the H2A–
H2B dimer belonging to another nucleosome, that was
detected in an X-ray analysis of tetranucleosomes pro-
ducing a zigzag structure (two-start helix) [28, 35].
Nucleosome depletion is characteristic of active
regulatory elements. In spite of their dynamic charac-
ter [5], nucleosomes prevent, to a certain extent, a free
access to DNA for various protein factors [36, 37]. To
bind to DNA, the majority of general and specific trans-
cription factors require that the regular nucleosome ar-
rangement on a DNA thread be locally disrupted to ge-
nerate a nucleosome-free region (NFR) or a nucleoso-
me-depleted region (NDR) [38, 39]. The regions are se-
veral hundreds of base pairs in size and can be mapped
as DNase I-hypersensitive regions [40–42]. Various re-
gulatory elements of the genome usually occur in NFRs
and NDRs [43–47]. It is possible to say that, compared
with the prokaryotic genome, the eukaryotic genome is
repressed on default and that transcription is regulated
largely by modulating the genome accessibility to trans-
cription machinery [48, 49].
First, the generation of NFRs and NDRs is neces-
sary for assembly of the preinitiation complex on a pro-
moter [50]; i. e., active promoters are always NDRs [39,
51]. It is typical of higher eukaryotes that chromatin re-
modeling complexes work to release the promoters from
nucleosomes [52, 53], as is considered below. Another
strategy is used in the case of Saccharomyces cerevisiae
constitutive promoters, where nucleosome occupancy
depends to a substantial extent on the DNA sequence
[50, 54]. Although the binding of the nucleosome core
to DNA is not sequence specific, there are sequences
that more or less preferentially interact with the histone
octamer and those where the octamer is usually not as-
sembled. The probability for a nucleosome to land on a
particular DNA sequence depends to a great extent on
the DNA flexibility, that is, the capability of wrapping
around the nucleosomal globule. A poly(dA:dT) tract
is one of the sequences that poorly bind with the nucleo-
some core [55]. A typical constitutive yeast promoter
contains a poly(dA:dT) tract flanked by two sequences
that preferentially bind nucleosomes and are known as
the nucleosome positioning sequences (NPSs) [51, 56].
The nucleosome-free region usually harbors binding
sites for transcription factors, which recruit transcrip-
tion initiation proteins to the promoter [57].
A chromatin remodeling strategy is commonly utili-
zed to establish and maintain the NDR in inducible S.
cerevisiae promoters (TATA-containing promoters) and
gene promoters of other eukaryotes examined [50]. A
key role is played in this case by active ATP-dependent
nucleosome displacement involving chromatin remo-
deling complexes [52, 53]. Various chromatin remode-
ling complexes move the nucleosome cores along a
DNA molecule, remove them from DNA, replace cano-
nical histones with variant ones, and perform several
other functions. Chromatin remodeling complexes of
the SWI/SNF and ISWI families play a main role in es-
415
NUCLEOSOMES AND TRANSCRIPTIONAL REGULATION
tablishing and maintaining NDRs [58, 59]. NDRs are
partly occupied by nucleosomes in S. cerevisiae upon
depletion of the RSC complex, which belongs to the
SWI/SNF family [60]. Transcription factors known as
the pioneering factors are the first to initially recruit the
chromatin remodeling complexes to cis-regulatory ele-
ments to establish an NDR [57, 61]. The pioneering fac-
tors differ from the majority of transcription factors in
being capable of recognizing their sites on nucleosomal
DNA. A small site for a pioneering factor can occur in
the linker between two positioned nucleosomes [62, 63].
Other pioneering factors are capable of competing with
nucleosomes for binding to DNA [61]. The pioneering
factors recruit either chromatin-remodeling complexes
or the enzymes that introduce certain posttranslational
modifications acting to recruit chromatin remodeling
complexes. A primary remodeling of the promoter re-
gion can open DNA to the binding of other transcrip-
tion factors, which similarly facilitate the NDR mainte-
nance and extension [64].
An association between the presence of NDRs and
the enrichment of chromatin regions with certain histo-
ne marks was demonstrated at the whole-genome level
in many studies [39, 65–68]. Among the histone post-
translational modifications that serve to recruit chro-
matin remodeling complexes, lysine acetylation in the
tail domains of histones H3 and H4 plays an essential
role and is high in active promoters [39, 65–68]. Nuc-
leosomes that incorporate histone H3 acetylated at K9
and/or K27 recruit the remodeling complexes with a
bromodomain, which recognizes these modifications
[69, 70]. Acetylation additionally acts to increase acti-
vity of the complexes recruited [71, 72]. Histone ace-
tyltransferase activity is inherent in many conserved
coactivator complexes, including SAGA, p300/CBP,
and TAF1 [73–75].
Along with high-level acetylation, the incorpora-
tion of variant histones H2A.Z and H3.3 in the vicinity
of an NDR seems to contribute substantially to nucleo-
some depletion from active promoters [65, 76]. Nucleo-
somes with H2A.Z and H3.3 are less stable [77] and fa-
cilitate the NDR maintenance by chromatin remodeling
complexes [78]. According to recent data, such nucleo-
somes are almost always present within NDRs as well,
being easily displaced from DNA by certain protein fac-
tors [21]. The H2A–H2B dimers are replaced with the
H2A.Z–H2B dimers by the Swr1 complex of the SWI/
SNF family in yeasts (and by its orthologs SRCAP and
p400 in Metazoa) [79, 80]. Swr1 is recruited to acetyla
ted nucleosomes and has affinity for nucleosome-free
DNA [81].
Enrichment in H3K4me3 is one of the most distinct
features of active promoters [39, 65–68]. The modifi-
cation probably maintains NDRs apart from its other
putative functions [82]. A characteristic location of
H3K4me3 in the 5' regions of genes is related to the me-
chanism of this modification. Histone methyltransfe-
rase Set1, which is conserved among all eukaryotes and
is responsible for H3K4 trimethylation, binds to the
Ser5-phosphorylated C-terminal domain of initiating
RNA polymerase [83, 84]. As the polymerase starts
elongation and the posttranslational modification profi-
le of its C-terminal domain changes (phosphorylation
at Ser2 rather than at Ser5), Set1 dissociates, and the
level of H3K4 methylation grows lower [36, 85]. A
transcription-independent mechanism is also possible
for H3K4 methylation in vertebrates. In vertebrates,
Set1 is recruited to the promoters of housekeeping ge-
nes and master regulators of cell differentiation by Cfp1:
the promoters occur in CpG islands, Cfp1 is capable of
recognizing nonmethylated CpG dinucleotides, and
both Cfp1 and Set1 are components of one complex,
COMPASS [86, 87]. Many chromatin remodeling com-
plexes have protein components that interact with
H3K4me3 (this modification is recognized by the PDH,
Chromo, Tudor, MBT, and Zf-CW domains of various
proteins [88]). For instance, H3K4me3-binding domains
are responsible for the recruitment to promoters of hu-
man proteins CHD1 and BPTF, which are components
of chromatin remodeling complexes and have homo-
logs in many eukaryotes [89]. Histone acetyltransfera-
ses (HATs) contained in the SAGA and NuA3 comple-
xes are similarly recruited to promoters as other compo-
nents of the complexes interact with H3K4me3 [90].
In higher eukaryotes, NDRs are associated not only
with promoters, but also with transcription factor-bin-
ding sites located in distant regulatory DNA elements,
of which enhancers and insulators are two main classes.
Distant regulatory elements, rather than promoters, ac-
count for the vast majority of regions where NDRs are
established in some or other cells in Metazoa [39, 66,
91]. Enhancers are sequences of several hundreds of ba-
416
GOLOV A. K. ET AL.
se pairs in length and harbor binding sites for several
transcription factors, which are responsible for specific
activation of enhancer-regulated genes [92, 93]. Enhan-
cers can be up to tens or hundreds of kilobases away
from their target promoters [39, 66, 94]. The distance is
even greater than 1 Mb in exceptional cases [95]. Enhan-
cers can occur both upstream and downstream of the
target promoters, in both intergenic regions and introns
[96, 97]. Cases were documented where enhancers are
in coding gene regions [98].
Enhancer NDRs are far more tissue specific than
promoter-associated NDRs [39, 66, 99]. A close rela-
tionship is assumed for the establishment of NDR and
the establishment of the enhancer-associated H3K4me1
mark at enhancers [39, 65, 66, 68]. Pioneering factors
recruit histone methyltransferases, which establish an
H3K4me1-enriched region at the enhancer [100]. In
turn, H3K4me1 recruits the p400 remodeling complex,
which incorporates H2A.Z in nucleosomes [101, 102].
H2A.Z-containing nucleosomes are unstable, and a
small NDR consequently forms at the so-called poised
enhancers [99, 103, 104]. Differentiation signals activa-
te the poised enhancers by targeting additional tissue-
specific transcription factors and signaling pathway ef-
fectors to them, and the factors expand the NDR by re-
cruiting and activating the chromatin remodeling and
coactivator complexes possessing HAT activity, inclu-
ding p300/CBP as a main one [93, 105]. A main target
of p300/CBP is H3K27, and its acetylation is thought to
provide a mark associated with active enhancers [99,
103].
Along with enhancers, cis-regulatory elements
known as the insulators colocalize with nonpromoter
NDRs. Insulators are thought to perform a broad range
of functions, the main of which are to prevent the exten-
sion of repressive chromatin marks (barrier activity)
and to block the action of an enhancer on a promoter
when interposed between them (enhancer-blocking ac-
tivity) [106–108]. Insulators can display either both ac-
tivities or exclusively enhancer-blocking activity in a
transgenic reporter assay. Enhancer-blocking activity
is due to binding sites for a special protein group known
as the insulator proteins. TFIIIC is one of the most con-
served insulator proteins, acting additionally as a gene-
ral transcription factor to facilitate RNA polymerase III
landing on DNA [109, 110]. CTCF also performs the
insulator function in vertebrates [111, 112]. Drosophila
has not only TFIIIC and a homolog of vertebrate CTCF
(dCTCF) to sustain enhancer-blocking activity of insu-
lators, but also a number of other proteins: Su(Hw),
GAF, BEAF-32, and Zw5 [113, 114].
Insulator NDRs are enriched in H3K4me1 and the
H2A.Z variant [68, 115]. The mechanism that establi-
shes and maintains NDRs at insulators is most likely si-
milar to that of enhancers. It should be noted that verte-
brate insulators are less variable than enhancers and that
their positions are more or less constant in different
cells [66]. This is possibly related to the fact that the
main vertebrate insulator protein CTCF occurs in all
cells and acts as a pioneering factor, autonomously bin-
ding to its sites in chromatin regardless of whether or
not they are free of nucleosomes [61, 116].
Several insulators and enhancers display RNA poly-
merase II binding and enrichment in H3K4me3, thus
being functionally similar to promoters [117–120]. The
appearance of these features correlates with enhancer
activation in certain cells [119, 121, 122]. Moreover,
such enhancers and insulators can be transcribed to yield
unstable noncoding RNAs. The functional significance
of their transcription is a matter of discussion [119, 122,
123].
Remodeling of nucleosomal particles during
transcription elongation. Nucleosomal particles pro-
vide an obstacle for elongating RNA polymerase II in
vitro [124, 125]. In vivo, histone chaperones and chro-
matin remodeling complexes improve the efficiency of
elongation [126, 127], facilitating local partial nucleo-
some disassembly in front of the polymerase. Active
transcription alters the regular nucleosome arrangement
along the transcription unit, and the alteration may ha-
ve adverse consequences for the cell, e. g., activating
cryptic promoters (see below) [128]. Special mecha-
nisms work to ensure correct chromatin assembly be-
hind the passing elongation complexes [127, 128]. As
the elongating RNA polymerase II complex progresses
along nucleosomal DNA, one of the H2A–H2B dimers
dissociates, while the residual histone hexamer remains
associated with DNA [124, 129]. This mechanism ac-
counts for a higher exchange rate of H2A–H2B dimers
on transcribed genes [130, 131]. The exchange rate of
the total nucleosome core increases with increasing
transcription intensity, indicating that (H3–H4)2 tetra-
417
NUCLEOSOMES AND TRANSCRIPTIONAL REGULATION
mers can also dissociate when elongating complexes
pass frequently [130, 132, 133]. H2A–H2B dimer ex-
change probably involves the Asf1, Nap1, Spt6, and
FACT histone chaperones, which act together with the
SWI/SNF and RSC chromatin remodeling complexes
[134-139]. Histone acetyltransferases PCAF and Elp3,
which stimulate the function of chromatin remodeling
complexes, specifically interact with elongating RNA
polymerase II [140, 141]. SAGA and NuA4 are also re-
cruited to transcription units along with the elongating
complex to stimulate nucleosome displacement [142,
143].
On the other hand, nucleosome destabilization in
transcribed regions increases probabilities of spontane-
ous formation of NDRs. Some of them may happen in
DNA regions allowing transcription initiation [144–
147]. These regions are known as the cryptic promo-
ters, and several mechanisms work to repress their acti-
vity. An important role is played by the Chd1 and Isw1
chromatin remodeling complexes, which maintain regu-
lar nucleosome spacing in transcribed regions [148–
151]. The interaction of H2A–H2B dimers with the
Asf1, Nap1, Spt6, and FACT chaperones facilitates the
restoration of a nucleosomal octamer as soon as the po-
lymerase has passed. In addition, dynamic acetylated
nucleosomes are stabilized as Rpd3, Hos2, and Hda1
histone deacetylases are recruited to transcribed regions
[152, 153]. The Rpd3S deacetylation complex plays a
key role in the process. RpdS3 is recruited by the Ser2-
phosphorylated C-terminal region of elongating RNA
polymerase II [152, 153]. Rpd3S activity is higher on
H3K36me3-containing nucleosomes, which interact
with the Eaf3 and Rco1 subunits of the complex via
the Chromo and PHD domains [152]. H3K36 trimethy-
lation, which recruits histone deacetylases, is catalyzed
by Set2 histone methyltransferase, which also interacts
with the Ser2-phosphorylated C-terminal domain of
RNA polymerase II [154, 155]. Thus, the modification
provides a specific mark for the bodies of actively trans-
cribed eukaryotic genes [156, 157] and ensures that
low-level histone acetylation is restored in gene bodies
as soon as the transcription complex has passed [128].
Internucleosomal interactions and the regulation
of transcription. A number of modifications occurring
in canonical histones and the presence of some variant
histones affect, to a certain extent, the strength of inter-
nucleosomal interactions. The modifications modulate
the chromatin packaging and thereby act as an important
factor regulating gene expression. When nucleosomal
particles that strengthen the internucleosomal contacts
are incorporated in chromatin, chromatin is condensed
and DNA becomes less accessible to transcription ma-
chinery, while nucleosome modifications that hinder
the internucleosomal interactions facilitate a loosening
of chromatin and activation of its genes. The latter group
of modifications includes H4K16 acetylation, which
prevents the N-terminal domain of histone H4 from in-
teracting with the acidic patch of the neighbor nucleo-
some. Chromatin composed of H4K16ac-containing
nucleosomes cannot produce 30-nm fibers in vitro [158–
160] and is probably depleted of lateral interactions
with other nucleosomal fibers in vivo. Nucleosome ace-
tylation at other lysines can also affect in part the stabi-
lity of internucleosomal interactions [161]. Local de-
condensation is possibly a mechanism that sustains the
activator effect of acetylation on regulatory DNA ele-
ments. A similar effect is known for the incorporation
of variant histone H2A.Bbd. This variant histone lacks
the amino acid residues that are involved in the for-
mation of the negatively charged surface (acidic patch)
to interact with H4K16 [162]. Paradoxically, variant
histone H2A.Z, which usually colocalizes with NDRs,
allows a greater acidic patch area as compared with ca-
nonical histone H2A, thus strengthening the internuc-
leosomal contacts [163, 164].
A special group of histone modifications includes
H3K9me3 and H3K27me3. Nucleosomes with these
modifications recruit specific architecture proteins,
which facilitate a denser chromatin packaging. The re-
sulting condensed chromatin clusters at the periphery of
the nucleus, in the perinucleolar region, and nucleoplas-
mic foci known as the chromocenters. Chromatin of
denser regions was termed heterochromatin as opposed
to less compact euchromatin [165].
H3K9me3 binds with heterochromatin protein 1
(HP1). HP1 is highly conserved, and its homologs are
found in the majority of eukaryotes with the exception
of budding yeasts [166], where a similar function is per-
formed by the SIR proteins [167]. HP1 binds to
H3K9me3 via its chromodomain, which is in the N-ter-
minal region of the protein. The C-terminal region of
HP1 harbors the so-called chromoshadow domain,
418
GOLOV A. K. ET AL.
which provides for HP1 oligomerization [168]. Thus,
HP1-mediated lateral interactions between H3K9me3-
containing nucleosomes lead to chromatin condensa-
tion [169]. In addition, HP1 is capable of recruiting his-
tone methyltransferases Suv39h1/2 and SETDB1, which
are responsible for H3K9 trimethylation [170]. The re-
sulting positive feedback is one of the mechanisms
spreading the «histone code signal» to produce exten-
ded H3K9me3-enriched domains [171, 172]. Hetero-
chromatin, which contains highly repetitive DNA and
is enriched in H3K9me3 and HP1, occurs in pericent-
ric and subtelomeric regions in the majority of euka-
ryotes. However, it should be noted that neither HP1
[173, 174] nor H3K9 trimethylation [175] is essential
for maintaining the heterochromatic chromocenters
containing pericentric DNA. In addition, H3K9me3
domains that usually correspond to individual silent
genes occur in chromosome arms. For instance, more
than 10,000 H3K9me3-enriched domains with a medi-
an size of approximately 7 kb were observed in human
embryonic stem cells (hESCs). Similar domains are
about twice as large in fibroblasts [176]. Genome-wi-
de studies identified the so-called LOCK (large orga-
nized chromatin K9 modification) domains, which are
extended (~ 100 kb) genome segments enriched in his-
tone H3 di- or trimethylated at K9 [177].
H3K27me3 is another conserved histone modifica-
tion characteristic of eukaryotic heterochromatin [178].
The modification is often associated with facultative he-
terochromatin on genes – master regulators of develop-
ment [178, 179]. The H3K27me3 establishment and
mechanism of action are closely associated with Poly-
comb group (PcG) proteins. PcG proteins are compo-
nents of several complexes, of which PRC1 and PRC2
are best understood. PRC2 uses its component histone
methyltransferase EZH2 to trimethylate histone H3 at
K27. PRC1 binds to H3K27me3 and is thereby associa-
ted with sites of PRC2 activity [180]. In Drosophila,
PRC2 is recruited to target genes by PRE elements (Po-
lycomb response elements) which harbor consensus
binding sites for several repressor factors interacting
with PRC2 [181–183]. In vertebrates, the mechanism
recruiting PRC2 to target genes is not fully understood
[180]. An important role in the process is most likely
played by CpG islands, where the promoters of genes
targeted by PcG complexes mostly occur in vertebrates
[184, 185]. These are usually the promoters of genes in-
volved in maintaining pluripotency and master regula-
tors of differentiation.
In embryonic stem cells, H3K27me3 colocalizes
with the activating mark H3K4me3 in the promoters of
master regulators of differentiation to produce the so-
called bivalent promoters [157]. Depending on the cell
lineage, one of the marks is removed during differen-
tiation, and if it is H3K27me3 the gene is activated [157,
186]. A specific recruitment of PRC2 to target promo-
ters was observed in plants, Arabidopsis thaliana in par-
ticular, but a consensus similar to Drosophila PRE was
not identified [187].
The mechanism of promoter repression via
H3K27me3 and the PRC complexes is presumably re-
lated to the fact that, like HP1, PRC1 causes chromatin
compaction to prevent free access of transcription fac-
tors to the genes involved [188–190]. According to clas-
sical views, heterochromatin is a more compact form of
chromatin, and its compaction prevents heterochroma-
tin DNA from being accessed by transcription machine-
ry and thereby facilitates repression of heterochromatic
genes. However, there is evidence that accessibility to
large protein factors is similar between euchromatin and
heterochromatin. For instance, the genome is more or
less uniformly accessible to Dam methylation regard-
less of the heterochromatin nature of particular regions
in Caenorhabditis elegans and S. cerevisiae [191, 192].
Transcription factors expressed artificially display no
preference in binding to their sites in heterochromatin
or euchromatin [191, 193]. Only molecular complexes
of more than 1 MDa are specifically excluded from he-
terochromatic regions according to microscopic studies
[194–197].
Accessibility of heterochromatin or even more com-
pact chromatin of metaphase chromosomes to diffusion
of large protein complexes is probably related to the dy-
namic character of internucleosomal interactions, as as-
sumed in the molten polymer model (see above). Owing
to this dynamic character, individual nucleosomal par-
ticles can locally move relative to each other in the three-
dimensional nuclear space and periodically create chan-
nels to allow migration of protein complexes within
compact chromatin domains [33, 197].
Transcriptional activity was recently demonstrated
for the majority of Drosophila genes located in HP1-
419
NUCLEOSOMES AND TRANSCRIPTIONAL REGULATION
enriched pericentric heterochromatin [193, 198, 199]. As
for genes repressed by the Polycomb complexes, it was
found that a preinitiation complex is assembled and
transcription initiated on their promoters in both Dro-
sophila and mammalian cells, but elongation is blocked
[200–202]. Thus, none of the most important types of
eukaryotic heterochromatin prevents access to chroma-
tin for transcription machinery. Then what is the role of
chromatin compaction? The role is explained by the mo-
del that architecture proteins, such as SIR and HP1, and
the PRC1 complex do not act to restrict access of ac-
tivator factors to DNA, but rather function to create nuc-
lear compartments with a high concentration of inhi-
bitory factors, which ensure repression via other mecha-
nisms [203, 204]. In the case of Polycomb-dependent
repression, the mechanism possibly consists in PRC1-
mediated recruitment of RING1b ubiquitin ligase, which
ubuquitinates histone H2A at K119, to promoters. The
modification stabilizes the interaction of H2A–H2B di-
mers with (H3–H4)2 tetramers, and the elongating RNA
polymerase complex cannot pass through these nucleo-
somes [18, 205]. In addition, a compact arrangement of
repressed genome regions in the nucleus makes it pos-
sible to limit free diffusion of inhibitory factors in the
nuclear space, preventing their nonspecific activity
[206]. Well-known examples of such compact regions
are provided by peripheral and perinucleolar hetero-
chromatin, chromocenters, and PcG bodies [190, 204,
207, 208].
Conclusions. The structure of nucleosomal partic-
les and its changes that accompany transcriptional ac-
tivation or repression have been studied for almost half
a century. This level of chromatin packaging is the most
fully understood. However, several basic shifts occur-
red in the apparently firm views of nucleosomes and in-
ternucleosomal interactions in the past decade. Among
these mini revolutions, the 30-nm fiber as an important
level of chromatin packaging was rejected and changes
were made to the classical views of the heterochromatin
structure and the mechanisms of heterochromatic gene
silencing. A drift from focusing on one or a few model
loci to probing the chromatin organization on a geno-
me-wide scale is one of the main trends in recent stu-
dies of the lower levels of eukaryotic DNA packaging.
Another trend is collating the genome-wide maps of se-
veral epigenetic features, primarily the distributions of
histone modifications, variant histones, and NDRs. Both
of the trends are implemented in large-scale collabora-
tion projects, of which ENCODE and modENCODE
are the best known. A combination of the resulting data
sets with information obtained by «C» methods for the
spatial organization of chromatin [209–211] and high-
resolution microscopy findings will probably yield a
comprehensive picture of DNA packaging in the nea-
rest future and will help to better understand how the
packaging mode is related to functional processes oc-
curring in the cell nucleus.
Acknowledgements. This work was supported by
the Russian Science Foundation (grant 14-14-01088).
Íóêëåîñîìíà óïàêîâêà åâêàð³îòíî¿ ÄÍÊ ³ ðåãóëÿö³ÿ òðàíñêðèïö³¿
À. Ê. Ãîëîâ, Ñ. Â. Ðàç³í, À. À. Ãàâðèëîâ
Ðåçþìå
ßäðà åâêàð³îòíèõ êë³òèí ì³ñòÿòü ãåíîìíó ÄÍÊ, ë³í³éí³ ðîçì³ðè
ÿêî¿ ó äåñÿòêè òèñÿ÷ ðàç³â ïåðåâèùóþòü ¿õí³é ä³àìåòð. Áàãàòî â
÷îìó òàêèé âèñîêèé ñòóï³íü êîìïàêòèçàö³¿ çàáåçïå÷óºòüñÿ óïà-
êîâêîþ ÄÍÊ ó õðîìàòèí, êëþ÷îâèì åòàïîì ÿêî¿ º íàìîòóâàííÿ
ÄÍÊ íà íóêëåîñîìí³ ãëîáóëè. Îêòàìåð ã³ñòîí³â, ÿê³ ñêëàäàþòü
íóêëåîñîìíó ãëîáóëó, âçàºìî䳺 ç ÄÍÊ çà ïîñåðåäíèöòâîì åëåêò-
ðîñòàòè÷íèõ êîíòàêò³â. ÄÍÊ-ã³ñòîíîâ³ âçàºìî䳿 äîñòàòíüî
ì³öí³ ³ óòðóäíþþòü äîñòóï äî íóêëåîñîìíî¿ ÄÍÊ áàãàòüîõ ôåð-
ìåíò³â ³ òðàíñêðèïö³éíèõ ôàêòîð³â. Ó òîé æå ÷àñ íàÿâí³ñòü íóê-
ëåîñîì íå ïåðåøêîäæຠïðîõîäæåííþ òðàíñêðèïö³¿ òà ³íøèõ
ïðîöåñ³â, ïîâ’ÿçàíèõ ç ðåàë³çàö³ºþ ãåíåòè÷íèõ ôóíêö³é ÄÍÊ.  îã-
ëÿä³ ðîçãëÿíóòî ñòðóêòóðó ³ ðîçìà¿òòÿ íóêëåîñîì òà ¿õíþ öåíò-
ðàëüíó ðîëü ó ðåãóëÿö³¿ òðàíñêðèïö³¿. Îñîáëèâó óâàãó ïðèä³ëåíî
çíà÷åííþ ì³æíóêëåîñîìíèõ âçàºìîä³é ó çàáåçïå÷åíí³ äîñòóïíî-
ñò³ ãåíîìó äëÿ òðàíñêðèïö³éíî¿ ìàøèíåð³¿, à òàêîæ ðåãóëüîâàíî-
ìó âèäàëåííþ íóêëåîñîì ç ðåãóëÿòîðíèõ åëåìåíò³â ³ òðàíñêðèï-
ö³éíèõ îäèíèöü â ïðîöåñ³ åëîíãàö³¿ òðàíñêðèïö³¿.
Êëþ÷îâ³ ñëîâà: õðîìàòèí, ìîäèô³êàö³¿ ã³ñòîí³â, íóêëåîñîìà,
òðàíñêðèïö³ÿ.
Íóêëåîñîìíàÿ óïàêîâêà ýóêàðèîòè÷åñêîé ÄÍÊ
è ðåãóëÿöèÿ òðàíñêðèïöèè
À. Ê. Ãîëîâ, Ñ. Â. Ðàçèí, À. À. Ãàâðèëîâ
Ðåçþìå
ßäðà ýóêàðèîòè÷åñêèõ êëåòîê ñîäåðæàò ãåíîìíóþ ÄÍÊ, ëèíåé-
íûå ðàçìåðû êîòîðîé â äåñÿòêè òûñÿ÷ ðàç ïðåâûøàþò èõ äèà-
ìåòð. Âî ìíîãîì òàêàÿ âûñîêàÿ ñòåïåíü êîìïàêòèçàöèè îáåñïå-
÷èâàåòñÿ óïàêîâêîé ÄÍÊ â õðîìàòèí, êëþ÷åâûì ýòàïîì êîòîðîé
ÿâëÿåòñÿ íàìàòûâàíèå ÄÍÊ íà íóêëåîñîìíûå ãëîáóëû. Îêòàìåð
ãèñòîíîâ, ñîñòàâëÿþùèõ íóêëåîñîìíóþ ãëîáóëó, âçàèìîäåéñòâó-
åò ñ ÄÍÊ ïîñðåäñòâîì ýëåêòðîñòàòè÷åñêèõ êîíòàêòîâ. ÄÍÊ-
ãèñòîíîâûå âçàèìîäåéñòâèÿ äîñòàòî÷íî ïðî÷íû è çàòðóäíÿþò
äîñòóï ê íóêëåîñîìíîé ÄÍÊ ìíîãèõ ôåðìåíòîâ è òðàíñêðèïöè-
îííûõ ôàêòîðîâ.  òî æå âðåìÿ íàëè÷èå íóêëåîñîì íå ïðåïÿòñò-
âóåò ïðîõîæäåíèþ òðàíñêðèïöèè è äðóãèõ ïðîöåññîâ, ñâÿçàííûõ
ñ ðåàëèçàöèåé ãåíåòè÷åñêèõ ôóíêöèé ÄÍÊ.  íàñòîÿùåì îáçîðå
ðàññìîòðåíû ñòðóêòóðà è ìíîãîîáðàçèå íóêëåîñîì è èõ öåíòðàëü-
420
GOLOV A. K. ET AL.
íàÿ ðîëü â ðåãóëÿöèè òðàíñêðèïöèè. Îñîáîå âíèìàíèå óäåëåíî çíà-
÷åíèþ ìåæíóêëåîñîìíûõ âçàèìîäåéñòâèé â îáåñïå÷åíèè äîñòóï-
íîñòè ãåíîìà äëÿ òðàíñêðèïöèîííîé ìàøèíåðèè è ðåãóëèðóåìîìó
óäàëåíèþ íóêëåîñîì ñ ðåãóëÿòîðíûõ ýëåìåíòîâ è òðàíñêðèïöèîí-
íûõ åäèíèö â ïðîöåññå ýëîíãàöèè òðàíñêðèïöèè.
Êëþ÷åâûå ñëîâà: õðîìàòèí, ìîäèôèêàöèè ãèñòîíîâ, íóêëåîñî-
ìà, òðàíñêðèïöèÿ.
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Received 12.10.14
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