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¹ Horikoshi Gene Selector Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation (JST), 5-9-6 Tokodai, Tsukuba, Ibaraki 300-2635, Japan
² Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

	Abstract

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
Chromosomes are partitioned into distinct functional regions. For example, heterochromatin regions consist of condensed chromatin and contain few transcriptionally active genes, whereas euchromatin regions are less condensed and majority of active genes reside in the euchromatin regions. Because distinct regions reside in each chromosome, borders are accordingly established between these regions. A prevailing view of the borders is that they are ‘walls’ that actively inhibit communication between distinct regions on chromosomes. Although little is known about the molecular bases of these walls, specific DNA elements are considered to recruit these walls to define the positions of the borders. We call the borders established with this mechanism as ‘fixed borders’. Past studies have identified various insulators (boundary DNA elements) that have been suggested to recruit fixed borders to them. Another mechanism, which we introduce and focus on in this review, does not require walls recruited by specific DNA elements at the chromosomal borders. Instead, the borders are defined by a balance of opposing enzymatic activities located at the opposite sides of the resultant borders. We name these borders ‘negotiable borders’. Here we review some of the recent progress in the field that offer valuable insight into mechanisms of establishing structural and functional borders on chromosomes.

	Overview of mechanisms of transcriptional regulation in eukaryotes

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
Mechanisms of eukaryotic transcriptional regulation enable selection of specific genes from thousands of genes or megabases of DNA. Three major processes assure highly specific regulation of transcription (Fig. 1). Large regions (over kilobases) of chromosomes, or sometimes whole chromosome, are inactivated and not transcribed (For recent reviews, see Richards & Elgin 2002; Grewal & Moazed 2003). The potential of genes to be transcribed is thus determined by the position on the chromosome, which is known as position effect variegation (PEV) of gene expression (Henikoff 1990). Inactivation of genes is considered a result of forming a tightly packed chromatin structure known as heterochromatin (Richards & Elgin 2002; Grewal & Moazed 2003). Specific chromatin structure prevents transcriptional activators from accessing the gene. Regions to be inactivated through this mechanism are often controlled in stage- or tissue-specific manners (Paro 1990). Understanding mechanisms to define these regions is thus crucial for understanding basic principles of gene expression and developmental processes.

View larger version (30K): [in this window] [in a new window]   Figure 1  The three major processes of specific regulation of gene expression. Subjects (left: chromosomes, nucleosomes, and transcription machineries) and related keywords (right) of the three major processes of transcriptional regulation are summarized (see text for details).

Another process is the transcription initiation reaction. This involves binding of DNA-binding transcription factors to specific DNA elements (Jacob & Monod 1961; Hochschild et al. 1983), assembly of transcription machineries on promoters (Horikoshi et al. 1988), and initiation of transcription reactions (Roeder & Rutter 1969). Genes transcribed through these processes often trigger succeeding transcription that enables cascade of efficient transcriptional regulation (Losick & Pero 1981; Davis et al. 1987).

Among these three processes, the latter two processes are well characterized mainly through biochemical reconstitution analyses. In contrast, molecular mechanisms of the first process to establish distinct chromosomal domains are not well understood. Because this process involves long regions of DNA, complex structures of chromosomes and a variety of regulatory factors, biochemical reconstitution analyses are difficult and the mechanisms are deduced mainly from genetical approaches. Understanding the mechanisms of this first process, however, is crucial to uncover the mechanisms of eukaryotic gene regulation, which will be the main topic of this review.

	Chromosome borders: partitioning chromosomes into distinct structural and functional regions

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
The eukaryotic chromosome consists of distinct structural and functional regions (Fig. 2). For example, the telomere or centromere is distinct from other regions to be protected from chromosome-end fusions or to enable proper chromosome segregations, respectively. From the viewpoint of gene expression, distinct regions can be classified into transcriptionally active and inactive regions. Because these two regions often reside adjacent to each other, the role of the border is important to prevent these two regions from inappropriate gene expressions.

View larger version (29K): [in this window] [in a new window]   Figure 2  Schematics of some chromosomal loci with distinct characteristics. Black lines are chromosomal DNA, orange circles as nucleosomal histones, green circles as DNA binding proteins (e.g. Rap1p, CENP-B) that bind to specific elements (e.g. silencer, CENP-B box; green boxes), and blue circles as chromatin binding proteins that establish specific chromosome structures (e.g. Sir2/3/4 complex, Swi6p). Telomeres are ends of chromosomes, that are protected from fusion between the ends. Centromeres are responsible for chromosome segregation. HM loci are models of heterochromatin-based silencing in S. cerevisiae. rDNA (ribosomal DNA) loci encode rRNAs and consist of highly repetitive sequences. rDNA loci are highly active in transcription but protected from recombination as well.

View larger version (21K): [in this window] [in a new window]   Figure 3  Summary of the prevailing view of chromosome borders. (a) Establishment of fixed borders (barrier and enhancer blocker). Boundary element or insulator is shown with green box, components recruited to the elements with green circles. These factors (shown with green) function as a barrier, an enhancer blocker or both. Modifications (e.g. acetylation) of chromatin are shown by yellow circle, promoters by grey boxes and enhancer by an orange box. The other objects are drawn as in Fig. 2. Barriers block spreading of inactive chromatin shown as being coated with specific proteins (blue circles in the middle panel). Enhancer blockers block communication between enhancers and promoters of transcription (in the lowest panel). (b) Suggested models for the mechanism by which insulators establish chromosome borders. In the upper panel, the chromosome border is established by attachment to nuclear architectures. In the lower panel, the border is established by specific state of chromosome modification at the insulator. In both models, effects of transcription enhancers or silencers cannot get over the established borders. The mechanisms by which the borders block the effects, however, cannot be explained by the models directly.

Over the past years, many insulators that can block the spread of transcriptionally active or inactive chromatin have been identified. For lists of DNA elements or involved protein components, a number of excellent reviews are now available (Bell & Felsenfeld 1999; Sun & Elgin 1999; Oki & Kamakaka 2002; West et al. 2002). In short, these identified insulators have been characterized under the basic concept of a fixed border that insulators establish fixed borders at their locations on chromosomes. According to their effects (i.e. whether they block spread of transcriptionally active- or inactive-chromatin), the insulators can be classified either as ‘enhancer blockers’ or ‘barriers’, respectively (Oki & Kamakaka 2002; West et al. 2002) (Fig. 3a). In this review, we introduce a novel view for establishing a chromosome border which we name ‘negotiable border’ (Horikoshi 2003) based on two opposing modifications of histone proteins (Kimura et al. 2002).

	Distinct chromosomal regions and distinct chromatin modifications

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
Histone modification which occurs on a fundamental component of a chromosome is an indicator for distinct chromosomal regions (Turner 2000; Strahl & Allis 2000). For example, acetylation of Lys-5 and Lys-8 of histone H4 is found in euchromatin regions, whereas acetylation of Lys-12 of histone H4 is found in heterochromatin regions in Drosophila (Turner et al. 1992). Modification of DNA itself is also an indicator on chromosomes in plants and mammals (Richards & Elgin 2002). Structural similarities between the substrates that share similar modification enzymes or between enzymes that share similar substrates have been found (Yamamoto & Horikoshi 1997; Kimura & Horikoshi 1998a,b; Adachi et al. 2002). These functional and structural correlations between modification of specific residues on histones and specific regulation of biological reactions led to and support a notion of ‘histone code’ that specific patterns of modification on histones trigger specific reactions on chromosomal regions (Turner et al. 1992; Turner 2000; Strahl & Allis 2000).

Establishment of borders between distinct regions on chromosome often involves establishment of borders of histone (or DNA) modifications. Consistent with this notion, loss of boundary elements results in loss of histone modifications within a specific region (Mutskov et al. 2002) or in spread of the modification state to neighbouring regions (Noma et al. 2001). The prevailing view for the relationship between chromosome border and chromatin modification is that fixed borders defined by insulators function as ‘walls’ to prevent spread of modification state into neighbouring regions. The molecular basis of how these walls prevent modifications from spreading remains to be elucidated although several models have been proposed (Fig. 3).

	Negotiable border: a novel view of chromosome border

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
‘Negotiable border’ is an alternative view for establishment of a chromosome border (Fig. 4)(Horikoshi 2003). Positions of negotiable borders are not defined strictly as those of fixed borders (Fig. 4a), but defined in a passive manner as a result of balance between two conflicting activities (e.g. acetylation and deacetylation, or acetylation and methylation, of identical lysine residue on a histone) located at both sides of the chromosome (Fig. 4b). Between two competing histone modification activities, an apparent gradient of histone modification is formed (Kimura et al. 2002). Although chemical modifications is an either-or choice, the transition from hyper-acetylated to hypo-acetylated states along the chromosome appears gradually rather than in a step-wise manner (Kimura et al. 2002; Suka et al. 2002). The observed gradient of modification may be a result of the sum up the variety of modification states differing among individual cells, or due to a limitation of resolution in the experiments.

View larger version (51K): [in this window] [in a new window]   Figure 4  Comparison between a fixed border (a) and a negotiable border (b). The orange lines indicate locations of the functional borders between two chromosomal regions (for example, transcriptionally competent and inactive regions). In (a), the borders are fixed on the ‘boundary element’, whereas those in (b) are negotiable according to the position of the ‘chromosomal gradient’ based on balance of the two chromosome modification activities. (c) Non-biological examples of a fixed border (left: the Berlin wall) and a negotiable border (right: the Battle of Sekigahara). The Battle of Sekigahara took place at the age of civil strife in Japan (1600 AD). The army from Osaka (the ‘Army of the West’) and that from Tokyo (the ‘Army of the East’) met and fought at Sekigahara, a place between Osaka and Tokyo. Other examples may be the Great Wall of China (fixed border) and the Civil War (negotiable border).

	Experimental support for negotiable border

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
Gene silencing in the budding yeast Saccharomyces cerevisiae is a good model to study the regulation of heterochromatin-like structure and thus establishment of chromosome border (Grunstein 1998) (Fig. 2). Chromatin in these regions contains hypo-acetylated histones and Sir proteins (Sir2p, Sir3p, and Sir4p). DNA binding protein Rap1p recruits Sir2p/Sir3p/Sir4p complex to initiate heterochromatin-like state that is inactive in gene expression. The regions are hypo-acetylated through function of Sir2p, a histone deacetylase (Braunstein et al. 1996; Imai et al. 2000). This hypo-acetylated form of histone becomes a platform for Sir3p to bind the chromosome (Johnson et al. 1990; Hecht et al. 1995; Carmen et al. 2002), which is the mechanism that enables heterochromatin to spread along the chromosome (Hecht et al. 1996; Grunstein 1998). A basic concept that specific modifications of chromatin regulate binding of specific molecules on to chromatin to establish a chromosomal region is conserved throughout eukaryotes (Grunstein 1998). Several DNA elements have been identified to block spread of silencing to neighbouring regions in S. cerevisiae (Bi & Broach 1999; Fourel et al. 1999; Pryde & Louis 1999; Donze & Kamakaka 2001). These DNA elements and associated proteins are thought to establish fixed borders on the chromosome. The extent to which telomeric silencing can spread along the chromosome can be modulated by overproducing Sir3p or inserting a strong transcriptional promoter into a telomere-proximal region (Aparicio & Gottschling 1994; Hecht et al. 1996). Although these experiments were intended to show the effect of increasing amount of the silencing protein (Sir3p) or the strong promoter on the spread of silenced region, we can interpret these data as implying that positions of the borders may not be fixed.

Recently, Sas2p and Sir2p have been found to function as a pair of HAT (histone acetylase) and HDAC (histone deacetylase), respectively, that act in concert to establish an apparent gradient of acetylation of Lys-16 of histone H4 along chromosomes in yeast telomeres (Kimura et al. 2002; Suka et al. 2002). Loss of either enzymatic activity leads to spread of the state of modification, localization of a telomere protein (Sir3p), and state of gene expression, across the original border. These results question the existence of a fixed border in this region and support that border formation is negotiable.

Noteworthy about these experiments are, firstly, that disrupting either enzyme (Sas2p or Sir2p) without manipulating DNA sequences around the border disrupted the original border, and, secondly, disrupting each enzyme with opposing function (Sas2p or Sir2p) had an opposite effect and relocated the position of the border back and forth along a chromosome. From the ‘fixed border’ viewpoint, the first result indicates that either Sas2p or Sir2p (or both) should be necessary for function of the wall itself (for example, an integral component of the wall) (Fig. 6a). However, considering that Sas2p-dependent hyperacetylation/gene-activation, and Sir2p-dependent hypoacetylation/gene-inactivation can both spread across the original border (second result), it is inappropriate to consider Sas2p or Sir2p (or both) functioning as a wall to prevent spread of the chromatin state. Instead, both enzymes act as if they are seeking to gain the other's ‘field’ (Figs 4c and 6b).

View larger version (20K): [in this window] [in a new window]   Figure 6  Anticipated results of the effect of disrupting histone modification enzymes. (a) In the ‘fixed border’ model, the state of histone modification does not cross the border. (b) In the ‘negotiable border’ model, the state of histone modification crosses the border. Example used for the chromosome gradient model was acetylation of Lys16 of histone H4 near telomere in yeast (Kimura et al. 2002; Suka et al. 2002).

	Applicability of ‘negotiable border’ to other regions/species

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
The mechanism of negotiable border formation found between telomere-proximal and telomere-distal regions in S. cerevisiae can be applied to other chromosomal regions and other species. In S. cerevisiae, inactivation of genes dependent on chromosome location is found in cryptic mating loci or ribosomal DNA locus (Fig. 2; Guarente 1999). Because Sas2p and Sir2p are involved in silencing at both loci (Reifsnyder et al. 1996; Guarente 1999; Meijsing & Ehrenhofer-Murray 2001), negotiable borders are expected to be established in these regions (H. Fukuda, T. Chimura, A.K. and M.H., unpublished observation). Sas2p and Sir2p as well as histones are evolutionarily conserved proteins that govern gene expression in chromosome-wide manners (Hilfiker et al. 1997; Rosenberg & Parkhurst 2002). Sas2p and Sir2p may thus act in concert to establish negotiable borders in species in addition to S. cerevisiae.

It is reasonable to consider that negotiable borders are not only established by Sas2p-related HATs and Sir2p-related HDACs competing for Lys16 of histone H4. A number of borders previously assumed to be fixed may be negotiable. Support for this notion will be discussed in the next section. Moreover, the idea of a negotiable border can be applied to chromosomal borders involving modification of multiple residues. For example, euchromatin regions in chicken and the fission yeast contain hyper-methylated Lys4 and hypo-methylated Lys9 of histone H3, whereas the adjacent heterochromatin regions contain hypo-methylated Lys4 and hyper-methylated Lys9 (Litt et al. 2001a; Noma et al. 2001). Borders of the modification states (e.g. hyper- and hypo-methylation) of distinct residues (e.g. Lys4 and Lys9 of histone H3) correlate well with each other in these regions. From a fixed-border-view, a border blocks the spread of multiple modifications at once and thus the borders of the modifications accord with each other. From a negotiable-border-view, ‘cross-talk’ (Fischle et al. 2003) between modifications at distinct residues makes the borders of multiple modifications accord with each other. For example, methylation at Lys4 of histone H3 inhibits methylation of Lys9 of histone H3 (Wang et al. 2001) and thus the borders between hyper- and hypo-methylated regions of Lys4 of histone H3 accord with those between hypo- and hyper-methylated regions of Lys9 of histone H3.

Chromosomal borders may not necessarily involve specific modifications of histones or DNA. Some insulators do not have any evidence to establish specific modifications. If we assume that modification of chromatin is the only molecular basis of a negotiable border, a border without apparent transition of chromatin modification may not be a negotiable one. From a negotiable-border-view, however, the possibility remains that negotiation between uncharacterized modifications on chromatin (histones, DNA, or other components) or unknown properties of chromosome may play a role in establishment of these borders.

	A novel view for enhancer blockers and barriers

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
Previous studies have identified a number of boundary DNA elements at loci in various species. Does this indicate that most chromosome borders are fixed borders, and not negotiable? Aren’t these DNA elements involved in negotiable borders? Upon considering the molecular mechanisms to establish negotiable borders, a straight-forward model is to assume two kinds of DNA elements, each of which recruits the opposing enzymatic activity (Fig. 5). Some of the previously identified boundary elements may be involved in establishing a negotiable border instead of a fixed border. In this case, each element does not establish a fixed border at the element but recruits histone (or DNA) modification enzyme(s) to establish a negotiable border somewhere between the element and a DNA element preexisting on the chromosome by recruiting the opposing enzymatic activities (Fig. 7). Because it is difficult to locate the exact positions of borders between distinct chromosomal regions, the previous analyses on the borders do not exclude the possibility that some borders are negotiable.

View larger version (28K): [in this window] [in a new window]   Figure 5  A model to establish a negotiable border. Localization of each of the pair of modification enzymes can be defined by specific DNA elements on chromosomes (step 1). Recruited by DNA binding proteins (DBPs) bound to the DNA elements (step 2), the enzymes are able to modify surrounding chromosomal regions on either or both sides (step 3). Border of the modification state is established somewhere between the two DNA elements. Distinct chromosome states are established according to the distinct modification states (step 4).

View larger version (25K): [in this window] [in a new window]   Figure 7  Recruitment of a chromosomal border by DNA elements (insulators): a negotiable border view and a fixed border view. (Lower) A DNA element can establish fixed borders on the elements as previously proposed (Litt et al. 2001a,b; Mutskov et al. 2002). (Upper) In the negotiable border view, the element recruits one of the pair of enzymes that establishes a chromosomal gradient. The enzyme positions the border not at the element but at a site near the element. Note that although DNA elements (orange boxes) are located at the same chromosomal positions, the positions of the borders (orange lines) are different between the two models.

The study from Donze & Kamakaka (2001) showed that recruitment of Sas2p near a silent mating locus functions as a barrier. As discussed above, Sas2p is the HAT that establishes negotiable border in concert with the function of the HDAC, Sir2p, near the telomere. From the viewpoint of the negotiable border model, the results from Donze & Kamakaka (2001) can be interpreted as follows. Recruitment of Sas2p did not establish a fixed border (i.e. a barrier) at the Sas2p-recruiting DNA element but established a negotiable border somewhere between the element and a Sir2p-recruiting element. In fact, such Sir2p-recruiting element (i.e. silencer element) exists in the assay done by Donze & Kamakaka (2001). The DNA element characterized as a barrier can establish a negotiable border somewhere between the element characterized as an enhancer blocker, rather than establishing a fixed border at the location.

	Partitioning chromosomes with negotiable borders: seeding, spreading and negotiation

Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
In the negotiable border model, specific DNA elements act as ‘seeds’ to nucleate specific modification states of chromosomes (Fig. 5). DNA elements previously characterized as enhancer blockers or barriers can function as these ‘seeds’ to establish negotiable borders instead of ‘walls’ to establish fixed borders. In future studies, it will be important to know whether DNA elements required for boundary formation function either as ‘seeds’ (negotiable border model) or ‘walls’ (fixed border model).

Specific modification states of chromosomes then spread from the seeds to neighbouring chromatin in the negotiable border model (Fig. 5). Repetition of specific DNA elements that recruit modification enzymes may define the range of spreading. Otherwise, spreading may depend on properties of chromosome modification enzymes themselves. For example, the SAGA-HAT complex acetylates proximal nucleosomes, while the NuA4-HAT complex acetylates a broader region of over 3kbp [PDB] in vitro (Vignali et al. 2000). Localization of modification enzymes can also spread along the chromosome. For example, deacetylation of histones by Sir2 (HDAC) can create binding sites for Sir2 (accompanied with Sir3 and Sir4) on chromatin that will lead to further spread of deacetylated chromatin and Sir2 localization (Grunstein 1998). Similarly, methylation of histones by Clr4 promotes Clr4 (accompanied with Swi6) to bind and spread along chromatin (Grewal & Moazed 2003). In the negotiable border view, processes of seeding and spreading are required to define chromosomal regions. The negotiable borders are defined passively as a result of seeding and spreading (Fig. 5).

Adding a ‘negotiable border model’ to pre-existing ‘fixed border model’ may help understanding not only mechanisms of heterochromatin formation and position effect variegation, but also different and more complex mechanisms in higher eukaryotes, such as gene expression from homeotic or globin gene clusters.

	Acknowledgements

 
We are grateful to Drs G. Felsenfeld, K. Ishihara, R. Kamakaka, M. Nakao, N. Saito, T. Suzuki and K. Ura for helpful discussions, H. Fukuda for help in preparing the figures. We thank Berlin's urban information service and Gifu city museum of history for permissions to use the images presented in Fig. 4(c). This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Exploratory Research for Advanced Technology (ERATO) of the Japan Science and Technology Corporation (JST).

	Footnotes

 
^aPresent address: Graduate School of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama 223-8522, Japan.

^* Correspondence: E-mail: horikosh{at}iam.u-tokyo.ac.jp

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Top Abstract Overview of mechanisms of... Chromosome borders: partitioning... Distinct chromosomal regions and... Negotiable border: a novel... Experimental support for... Applicability of... A novel view for... Partitioning chromosomes with... References

 
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