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Expression-State Boundaries in the Mating-Type Region of Fission Yeast
Geneviève Thona, Pernilla Bjerlingb, Camilla Marie Bünnera, and Janne Verhein-Hansenaa Department of Genetics, Institute of Molecular Biology, University of Copenhagen, DK-1353 Copenhagen K, Denmark
b Karolinska Institute, Södertörn University College, S-14104 Huddinge, Sweden
Corresponding author: Geneviève Thon, Institute of Molecular Biology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353 Copenhagen K, Denmark., gen{at}biobase.dk (E-mail)
Communicating editor: G. R. SMITH
 | ABSTRACT |
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A transcriptionally silent chromosomal domain is found in the mating-type region of fission yeast. Here we show that this domain is delimited by 2-kb inverted repeats, IR-L and IR-R. IR-L and IR-R prevent the expansion of transcription-permissive chromatin into the silenced region and that of silenced chromatin into the expressed region. Their insulator activity is partially orientation dependent. The silencing defects that follow deletion or inversion of IR-R are suppressed by high dosage of the chromodomain protein Swi6. Combining chromosomal deletions and Swi6 overexpression shows that IR-L and IR-R provide firm borders in a region where competition between silencing and transcriptional competence occurs. IR-R possesses autonomously replicating sequence (ARS) activity, leading to a model where replication factors, or replication itself, participate in boundary formation.
MOST current models of genomic organization in eukaryotes involve specialized DNA elements, such as insulators or boundaries, whose role is to partition chromosomes into domains with different transcriptional states (for review, see 
The chromosomal region that contains the silent mat2 and mat3 mating-type cassettes of fission yeast is in many respects similar to heterochromatic regions of higher eukaryotes. Reporter genes artificially placed into that region are subject to a position effect by which transcription is stringently repressed (
and HP1ß proteins with chromatin modified by SUV39H1, a human Clr4 homolog (
Three cis-acting elements are believed to attract silencing complexes to the mating-type region (Fig 1A). Two of the elements are contained within a few hundred base pairs of each silent cassette (
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When modeling silencing in the mating-type region, one envisions that unidentified proteins, possibly products of the esp (
Neither the length of the silenced mating-type region nor the mechanisms that determine that length are known. According to all available evidence, silencing affects the 11-kb DNA segment that separates the two silent mating-type cassettes in addition to the mating-type cassettes themselves. At 15 kb on the centromere-proximal side of the mat2 cassette is the active mat1 mating-type cassette, a locus whose transcriptional activity has been well characterized (
5 kb from the centromere-proximal side of the mat2 cassette. The position of the centromere-distal edge of the silenced region was not determined, the first active gene identified in that region being his2, some 26 kb centromere-distal to mat3.
In addition to the elements mentioned above, a 2-kb inverted repeat is found in the mating-type region of S. pombe (G. THON, unpublished observations; Sanger Center S. pombe sequencing project; 16 kb. The IR-L and IR-R repeats are identical in sequence for a length of 2067 bp. They appear to contain no open reading frame (ORF). Rather, they have features characteristic of intergenic regions of low complexity, such as an AT content of 69%. The homology between IR-L and IR-R stops abruptly on each side of the identical core, the region of perfect homology on the side distal to the cassettes ending within G(A)3-6 tracts of 21 (IR-L) or 32 bp (IR-R). The pattern of histone H3 methylation at lysines 4 and 9 changes abruptly at IR-L and IR-R (
We report here that IR-L and IR-R colocalize with the edges of the silenced region. We examine their properties in the context of the mating-type region and show that they confer autonomous replication to a plasmid, which suggests that proteins involved in replication, or replication itself, take part in boundary function.
| MATERIALS AND METHODS |
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Yeast media and culture conditions:
YES (
Construction of S. pombe strains:
All chromosomal integrations were performed using the lithium acetate method (
The plasmids listed below were used to integrate ura4+ at sites described by their nucleotide position (nuc.) in GenBank sequences and shown in Fig 1B. ori1 refers to an integration of ura4+ with its promoter centromere-proximal whereas ori2 refers to ura4+ with its promoter centromere-distal. pGT234 (ori1) or pGT235 (ori2) were used to introduce ura4+ at XmnI (nuc. 34563 in AL035065); pAK67, at the XbaI site distal to mat2-P (nuc. 414 in U57841;
IR-R was deleted by replacing the mat3-M (XbaI)::ura4+ allele with a construct containing a 2.1-kb deletion between XbaI (nuc. 4017 in AL353012) and XmnI (nuc. 6136 in AL353012), pGT226. IR-R was inverted in the same fashion, using a construct containing an inversion of the 2.1-kb XbaI-XmnI fragment, pGT243. IR-L was deleted by replacing the (XmnI):: ura4+ mat2-P allele with a construct lacking nuc. 35002 in AL035065 to nuc. 328 in AL353012 (pGT236) or inverted by replacing the deleted nucleotides with the 2.1-kb XbaI-XmnI IR-R fragment (pGT244).
The BlpI site at nuc. 6994 of AL353012 was used to insert the 2.1-kb XbaI-XmnI IR-R fragment in either orientation or a 1.9-kb BstEII fragment of 
DNA. These insertions were combined with ura4 at the mat3-M centromere-distal SpeI (nuc. 6552 in AL353012) or BamHI site (nuc. 7386 in AL353012). pGT289 contains (SpeI)::ura4+ori1 (BlpI)::IR-R; pGT290, (SpeI)::ura4+ori2 (BlpI)::IR-R; pGT287, (SpeI)::ura4+ori1 (BlpI):: inv-IR-R; pGT288, (SpeI)::ura4+ori2 (BlpI)::inv-IR-R; pGT291, (SpeI)::ura4+ori1 (BlpI)::DNA; pGT292, (SpeI)::ura4+ori2 (BlpI):: DNA; pGT283, (BlpI)::IR-R (BamHI)::ura4+ori1; pGT284, (BlpI)::IR-R (BamHI)::ura4+ori2; pGT282, (BlpI)::inv-IR-R (BamHI):: ura4+ori1; and pGT281, (BlpI)::inv-IR-R (BamHI):: ura4+ori2.
Spot tests:
Five microliters of 10-fold serial dilutions of cell suspensions were spotted on the indicated selective media and on nonselective media (AA and MSA; not shown). The efficiency of plating on the nonselective media was in each case the same as the highest efficiency of plating on selective media.
Quantitation of ura4 transcripts:
RNA preparation, Northern blotting, and hybridization to a ura4 riboprobe were performed as described previously (
Overexpression of Swi6:
The swi6 ORF was amplified from pAL2 (
Test for ARS activity of IR-R:
The 1.8-kb ura4+-containing HindIII fragment (108 SP837 cells (h90 ura4-D18 leu1-32 ade6-M216) with the lithium acetate method (
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| RESULTS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The two inverted repeats, IR-L and IR-R, colocalize with the edges of the silenced mating-type domain:
We monitored gene expression in the mat2-mat3 region, with a special focus on the regions surrounding IR-L and IR-R. As had been done in previous studies (
The inverted repeats IR-L and IR-R are essential for accurate separation between expressed and silenced chromatin:
Whether IR-L or IR-R have a functional role in transcriptional silencing was investigated by deletion analysis. IR-L, IR-R, or both elements were deleted from the chromosome and the expression of the ura4 marker was assayed in strains carrying these deletions. Deletion of IR-L or IR-R resulted in an increased expression of ura4 at sites located near the edges of the normally silenced region (Fig 1B, compare row 5 with 20 and 9 with 37; Fig 1C, compare lanes 5 and 6 with 1 and 2). In each case, the effect was local, repression being released preferentially close to the deletion. Simultaneous deletion of IR-L and IR-R led to release of repression at both edges, the effect at each edge being no stronger than that caused by the individual deletion of its flanking element (Fig 1B, compare row 5 with 44 and row 9 with 48; Fig 1C, compare lanes 5 and 6 with 7 and 8). In addition, a slight derepression was observed at internal sites (Fig 1B, compare rows 6–8 with 45–47).
A more subtle effect of deleting IR-L or IR-R could be observed on FOA-containing medium. In the presence of IR-L and IR-R, ura4 placed at one of the outer insertion sites is uniformally expressed, in a fashion that allows no detectable growth on FOA-containing medium (Fig 1B, rows 3 and 4). This is, for example, observed at the mat2 centromere-proximal XmnI site. FOA-resistant cells with ura4 at this site are very infrequent and they consistently contain mutations in ura4 (data not shown). Following deletion of IR-L, an increased fraction of cells with ura4 at the XmnI site acquired the ability to form colonies in the presence of FOA (Fig 1B, rows 18, 19, 42, and 43). ura4 was epigenetically repressed in these cell lineages rather than mutated as found by replating (data not shown). Similarly, following deletion of IR-R, ura4+ placed in the normally well-expressed region on the mat3-M centromere-distal side could be silenced in a fraction of the cell population (Fig 1B, rows 38–41 and 49–52; data not shown). The fraction of cells affected was, however, very small, and Northern blot analysis revealed no changes in the level of ura4+ transcript originating from the mat3-M-distal SpeI or BamHI insertion sites (Fig 2C), indicating that, in most cells, deletion of IR-R does not lead to spreading of heterochromatin.
The deletion analysis of IR-L and IR-R shows that the two elements normally participate in the repression of transcription observed in the chromosomal region surrounding mat2 and mat3. They might act as unidirectional silencers whose action would be directed toward the mating-type cassettes, or they might function as insulators. Our observations are consistent with their major role being preventing the expansion of an expressed state from regions flanking the silenced region into the silenced region. However, they also reduce the spreading of silencing into transcriptionally active regions, an observation supported by further experiments involving the overexpression of the chromodomain protein Swi6 (see below). The two elements IR-L and IR-R can accomplish these functions independently of each other. Whether they act simply as spacers between regions that have adopted opposite and competing states of expression or whether they have a more active role that is dependent upon their particular sequence is addressed in experiments described below.
Translocation of IR-R away from mat3-M expands the silenced chromosomal region:
IR-R was moved from its wild-type chromosomal location to a more centromere-distal location, in the region that is normally expressed. More specifically, the element was moved 850 bp to a BlpI restriction site located between an SpeI and a BamHI restriction site (Fig 2A), at which the ura4 reporter gene had previously been integrated and found to be expressed (Fig 1B, rows 12–15; Fig 1C, lanes 9, 10, 13, and 14). Following the placement of IR-R between the SpeI and BamHI sites, a significant repression of ura4 was observed at SpeI (Fig 2B, rows 3 and 4; Fig 2C, lanes 3 and 4) while expression at BamHI was unaltered (Fig 2B, rows 11 and 12). A fragment of DNA of similar size originating from the bacteriophage had no repressive effect (Fig 2B, compare rows 7 and 8 with 1 and 2; Fig 2C, compare lanes 7 and 8 with 1 and 2). Hence, the IR-R element positions the edge of the silenced region. It does not simply provide spacing between silenced and expressed regions, but rather some specific aspect of its sequence is required for its effects.
An inverted IR-R element also blocks the spreading of active chromatin:
Because they are placed as inverted repeats, IR-L and IR-R face the silenced region in the same fashion. That orientation might be coincidental, or it might reflect a functional requirement, as it would, for example, if IR-L and IR-R were unidirectional silencing elements. If this were the case, changing their orientation would lead to transcriptional repression on the normally expressed side. The orientation of IR-L and IR-R relative to each other could also determine their degree of efficiency. In this case, inverting one element at a time might perturb its function whereas inverting them both at once might be less detrimental.
We examined first the effects of inverting IR-R. We inverted it at its normal chromosomal location (Fig 3) or at the BlpI site mentioned above (Fig 2). Similar observations were made in both cases. First, ura4 placed at sites centromere-distal to IR-R was always well expressed, indicating that IR-R does not act as a simple unidirectional silencing element. Second, ura4 placed at sites centromere-proximal to an inverted IR-R element achieved a level of repression intermediate to that conferred by IR-R in its wild-type orientation and that observed in the absence of IR-R. This was observed for ura4 at the EcoRV site close to mat3 in the case of the inversion of IR-R at its wild-type location (compare Fig 3A, row 7, with Fig 1B, rows 9 and 37; and in Fig 3B, compare lanes 3 and 4 with 5 and 6) or for ura4 at the SpeI site in the case of the inversion of IR-R at the BlpI site (Fig 2B, compare rows 5 and 6 with 1 and 4; Fig 2C, compare lanes 5 and 6 with 1 and 4). Hence, IR-R has the ability to strengthen silencing on its heterochromatic side when placed in either orientation, the wild-type orientation being slightly more effective than the reverse.
Since the effect of IR-R was partially orientation dependent, we tested whether inverting IR-L and IR-R in the same chromosome would lead to an increased repression at the sites affected by the inversion of IR-R. We found that this was not the case (Fig 3A, compare, for example, rows 7 and 18; Fig 3B, compare lanes 7 and 8 with 5 and 6). This supports our previous conclusion derived from the deletion analysis, that IR-L and IR-R can function independently of each other.
Duplication of IR-R leads to variegated boundary formation:
We duplicated the mat3-M boundary element by inserting a second copy of IR-R centromere-distal to the endogenous IR-R element (Fig 4). The second copy of IR-R was introduced in either orientation at the BlpI site. We monitored gene expression between the endogenous and duplicated IR-R elements, at the SpeI site used previously. We found that insertion of an IR-R copy in the wild-type orientation allowed expansion of the silent state past the endogenous IR-R element toward the telomere in a fraction of the cell population (Fig 4). No repression was observed in a swi6- background (data not shown), suggesting the repression was due to an extended chromosomal coverage by Swi6. Insertion of a spacer fragment of DNA or insertion of the IR-R element in the opposite orientation did not lead to repression of ura4 at SpeI (Fig 4, rows 3–6). Some FOA-resistant cells were present in strains with the inverted duplication of IR-R (Fig 4, rows 3 and 4). However, these FOA-resistant cells had lost the ability to mate or sporulate. Using Southern blot analysis, we determined the loss was due to recombination events between IR-L and inv-IR-R, which removed ura4 together with the entire mat2-P-mat3-M region (data not shown).
In the absence of such rearrangements, cells with the inverted IR-R element were not able to grow on FOA-containing plates. Hence, the repression of ura4 at the SpeI site appears to show strong dependence on the orientation of the IR-R element introduced at BlpI when the endogenous IR-R is present (Fig 4, lanes 1–4). The orientation dependence appears much weaker when the endogenous IR-R element is absent (Fig 2, lanes 3–6). This difference possibly reflects the ability of the endogenous IR-R element to partially block silencing (compare growth in the absence of uracil in Fig 2, lanes 3 and 4, and Fig 4, lanes 1 and 2).
The chromodomain protein Swi6 competes with active chromatin formation in cells lacking boundary elements:
The chromodomain protein Swi6 is probably the most extensively characterized of the S. pombe silencing factors. It can oligomerize and associates with heterochromatic regions over long stretches of DNA, suggesting that it spreads over the silenced regions (
In a first set of experiments, we examined the effects of Swi6 overexpression on transcriptional silencing at the mat3 centromere-distal EcoRV site. The ura4 reporter is repressed at that site in the presence of IR-R, partially repressed in the presence of an inverted IR-R element, and derepressed in the absence of IR-R. We found that overexpression of Swi6 could partially suppress the silencing defects caused by deleting or inverting IR-R (Fig 5A).
In a second set of experiments, we examined the ability of Swi6 to expand the silenced domain in the mat2 centromere-proximal region and whether that ability depended on the presence of IR-L. ura4 is normally well expressed when placed at the mat2 centromere-proximal XmnI site (Fig 1B, rows 3 and 4). Increased concentrations of Swi6 had no detectable effect at that site in the presence of IR-L and a repressive effect when IR-L was deleted (Fig 5B). These phenotypes confirm that the IR-L and IR-R elements can reduce the expansion of heterochromatin in addition to that of euchromatin. They also demonstrate that Swi6 becomes locally limiting in the mating-type region in the absence of IR-L or IR-R.
IR-R confers autonomous replication to a plasmid:
S. pombe autonomously replicating sequences (ARS) are several hundred base pairs long and AT-rich, with clusters of A and T residues (
| DISCUSSION |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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We have presented evidence that the IR-L and IR-R repeats mark the edges of the silenced mating-type region of fission yeast (Fig 7A). The limits of transcriptional repression coincide with the limits of a specialized chromatin structure in which histone H3 is hypermethylated at lysine 9 and hypomethylated at lysine 4 and that is associated with the chromodomain protein Swi6 (
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We found that IR-L and IR-R have a dual effect under normal physiological conditions. First, they prevent the spreading of the neighboring transcription competence into the silenced region. Consequently, one phenotype of an IR-L or IR-R deletion is a reduced repression of markers near the deleted repeat. Second, IR-L and IR-R block the spread of silencing. Following deletion of IR-L or IR-R, a ura4+ marker located outside of the normally silenced region can be repressed, allowing papillation on FOA (Fig 1B, compare, for example, rows 3 and 4 and 18 and 19, 31 and 32 and 42 and 43, 12–15 and 38–41, and 27–30 and 49–52). Although the repression takes place in only a small fraction of the cell population, the silenced state is partially stable once established, allowing improved growth on FOA (data not shown). The ability of IR-L or IR-R to block the expansion of silencing becomes more obvious in conditions where the Swi6 protein is overexpressed. Under these conditions, marker genes centromere-proximal to IR-L are frequently inactivated in cells lacking IR-L, but not in cells containing IR-L (Fig 5B). Taken together, these phenotypes indicate that IR-L and IR-R act as insulators between competing states of expression. The possibility that deleting IR-L or IR-R might decrease silencing was overlooked in the chromatin study of
Several models that are not mutally exclusive can account for the ability of a DNA element to prevent the spreading of active or repressive chromatin (for review, see, e.g.,
Alternatives, or additions, to looping models propose that nucleoprotein structures formed on boundary elements create discontinuities in the nucleosome array or in arrays of chromatin-associated proteins, thereby blocking processive activities such as the oligomerization along the DNA fiber of proteins required for either silencing or transcription. Many unrelated proteins could have that effect when complexed with DNA, accounting for the diversity of insulator elements found in Saccharomyces cerevisiae and other organisms (
IR-R promoting replication in plasmids raises the possibility that IR-L and IR-R also initiate DNA replication in the chromosome. By acting as origins, they might ensure that the region separating them is replicated at a time suitable for silencing. If IR-R is an active origin, the phenotype created by its duplication, which reduces the boundary activity of the endogenous IR-R element, could be due to origin interference, a phenomenon by which origins of replication suppress initiation of replication at nearby origins (
S. pombe origins of replication lie preferentially in intergenic regions. They are associated with promoters rather than with regions downstream of ORFs (
| ACKNOWLEDGMENTS |
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We thank our colleagues and friends for their critical input and editorial suggestions, especially Stanley Brown, Klavs Riishede Hansen, Inga Sig Nielsen, and Gerry Smith. The reported work was supported by grants from the Novo Nordisk Foundation and from the Carlsberg Foundation.
Manuscript received November 26, 2001; Accepted for publication March 27, 2002.
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