Eukaryotic chromatin is remodelled by the evolutionarily conserved Snf2 family of enzymes in an ATP-dependent manner. Several Snf2 enzymes are part of CRCs (chromatin remodelling complexes). In the present review we focus our attention on the functions of Snf2 enzymes and CRCs in fission yeast. We discuss their molecular mechanisms and roles and in regulating gene expression, DNA recombination, euchromatin and heterochromatin structure.

Introduction

Chromatin structure is modulated by remodelling enzymes belonging to the Snf2 family ATPases. In the present review, we compile the current knowledge of Snf2 enzymes and their functions in the fission yeast model system.

In eukaryotes, DNA is condensed inside the nucleus in the form of chromatin. The basic unit of chromatin is the nucleosome where 147 bp of DNA is wrapped around an octameric histone core. The dynamic balance between accessibility and inaccessibility of chromatinized DNA is regulated by a class of ATPases belonging to the SNF2 family, which are conserved from yeast to humans. Maintenance of this balance is critical for execution of all DNA-dependent biological processes, i.e. DNA replication, transcription, repair and recombination without perturbing the genome stability. Many of the SNF2 enzymes are part of large protein complexes called CRCs (chromatin remodelling complexes). These SNF2 enzymes serve as the catalytic subunit of the CRCs. Other SNF2 enzymes do their work alone without auxiliary proteins. SNF2 enzymes and CRCs regulate localized histone–DNA interactions by multiple mechanisms (Figure 1). This leads to either sliding or spacing of nucleosomes, exchange of histone variants or disassembly of nucleosomes. Such functions are often controlled by different subdomains in the catalytic subunit and/or subunits associated with the catalytic subunit in CRCs. The present mini-review is focused on bringing together the current knowledge of SNF2 enzymes, CRCs and their functional roles in fission yeast, Schizosaccharomyces pombe.

Overview of different chromatin remodelling events

Figure 1
Overview of different chromatin remodelling events

The outcome of chromatin remodelling by CRCs results in nucleosome sliding, high/low histone turnover, uniform spacing of nucleosomes, histone eviction and histone exchange.

Figure 1
Overview of different chromatin remodelling events

The outcome of chromatin remodelling by CRCs results in nucleosome sliding, high/low histone turnover, uniform spacing of nucleosomes, histone eviction and histone exchange.

Classification and functions of the SNF2 family of ATPases

The SNF2 family of ATPases belongs to superfamily 2 of helicases, which is characterized by unique conserved motifs present in the catalytic core of the helicase domain [1]. Unlike other helicases, SNF2 enzymes have lost their ability to unwind duplex DNA, but utilize ATP to translocate along the DNA to disrupt histone–DNA contacts and generate superhelical torsion. SNF2 proteins were classified on the basis of the differences in amino acid conservation and insertions within the SNF2-like helicase domain [1]. The S. pombe genome contains 20 SNF2-encoding genes, which are broadly grouped under five subfamilies: Snf2-like, Swr1-like, Rad54-like, Rad5/16-like and SSO1653-like. Several ATPases are categorized within each subfamily depending on their biochemical activities and helicase sequence conservation. A complete description of the SNF2 enzymes in S. pombe and a summary of their functions is provided in Table 1.

Table 1
Classification and functions of Snf2 enzymes in S. pombe

The ISWI subfamily is absent from S. pombe. *Catalytic subunit of each complex; **telomere-specific SHREC subunit; ***HP1 homologue associated with SHREC is also called SHREC2.

 
 

Swi/Snf

The S. pombe Snf21 and Snf22 enzymes were identified as the budding yeast, Saccharomyces cerevisiae, Sth1 (RSC complex) and Swi2/Snf2 (SWI/SNF complex) homologues with strong amino acid sequence similarities and protein domain conservation [24]. Snf21 is essential for cell viability, since the null mutant strain undergoes only a few rounds of cell division, and a temperature-sensitive snf21 mutant shows severe defects in chromosome segregation and cytokinesis [2,5]. The snf22+ gene, on the other hand, is a non-essential gene and its deletion severely affects chromatin remodelling, histone acetylation, transcriptional response to osmotic stress, expression of the invertase (inv1+)-encoding gene and meiotic recombination [3,6,7]. Localized chromatin remodelling by Snf22 at the ade6-M26 locus is essential for recruiting the DSB (double-strand break) machinery to chromatin and hence activating the meiotic recombination hotspot [3].

Affinity purification and MS analysis revealed that S. pombe SWI/SNF and RSC complexes consist of 12 and 13 subunits respectively, where four subunits (Ssr1, Arp9, Ssr2 and Ssr3) are shared between the two complexes [4,5] (Table 1). Further genetic characterization showed that SWI/SNF-specific subunits are not essential for cell viability, corroborating earlier in vivo findings. In contrast, deletion of some of the RSC-specific subunits is lethal to the cells, showing that the RSC complex is essential for cell survival [5]. It is possible that these subunits are essential for maintaining the integrity of the RSC complex. Interestingly, expression analysis revealed that SWI/SNF is generally involved in both activation and repression of transcription, whereas the RSC complex regulates genes encoding membrane and organelle proteins as well as developmental genes [5].

Chd1

The CHD1 (chromodomain, helicase, DNA-binding domain) family of SNF2 enzymes bears tandem CDs (chromodomains) at the N-terminus, a centrally located SNF2 type ATPase domain and two structurally related DNA binding SANT/SLIDE domains at the C-terminus [8]. Unlike budding yeast CHD1, fission yeast has evolved to possess two CHD1 paralogues called Hrp1 (helicase-related protein 1) and Hrp3. Hrp1 was first characterized as a negative regulator of cell growth and as being required for proper mitotic chromosome segregation [9,10]. Further characterization revealed several important functions of Hrp1 in transcription termination, transcriptional silencing at mating type and centromeres, nucleosome disassembly at promoters, nucleosome spacing in coding regions, and loading of CENP-A (centromere protein A) at the centromeres and at some gene promoters [1115]. Hrp3, on the other hand, is involved in transcriptional repression at mating type loci and regular spacing of the nucleosomes in coding regions [1619]. Interestingly, local chromatin remodelling by Hrp3 at ade6-M26 stimulates meiotic recombination, whereas Hrp1 remodelling activity suppresses recombination [6]. An intriguing question is how do these two closely related proteins perform specialized functions? Understanding the chromatin remodelling mechanisms of Hrp1 and Hrp3 will probably give insights into their distinct and redundant functions. To this end, we and others have shown two seemingly opposing mechanistic functions of Hrp1 and Hrp3; nucleosome disassembly at promoters and TSSs (transcription start sites) in concert with Nap1 [13] and regular spacing of nucleosome within gene bodies to prevent cryptic antisense transcription [16,18,19]. Therefore we hypothesize that disassembly of nucleosomes at promoters and TSSs will support transcriptional activation of a gene, whereas nucleosome assembly and spacing is critical during the passage of elongating RNA polymerase. These functions are important to support initiation and elongation by Pol II (polymerase II) by generating proper chromatin configurations. In addition, a role for Hrp1 in transcription termination has been demonstrated [11]. Hence there is evidence for three different stages of the Pol II transcription cycle (initiation, elongation and termination) being affected by Hrp1.

Interestingly, CHD1 in budding yeast has been implicated in maintaining high nucleosome turnover at gene promoters and 5′ coding regions and low turnover at 3′ coding regions of genes [20]. Similarly, in fission yeast the Hrp1 enzyme seems to have opposite effects on nucleosome stability in gene promoters compared with coding regions. As mentioned above, Hrp1 and Hrp3 are involved in the assembly of regularly spaced nucleosomes in coding regions [18]. At gene promoters, however, it has been suggested on the basis of in vivo experiments that the concerted action of topoisomerase I and Hrp1 stimulates nucleosome disassembly [14]. Further investigations of the remodelling functions of Hrp1 and topoisomerase 1 in vitro are needed to test this hypothesis.

Mi-2

Mi-2 is yet another class of SNF2 enzymes with one member in fission yeast, i.e. Mit1 (Mi-2-like interacting with Clr three 1). Mit1 is a subunit of SHREC [SNF2/HDAC (histone deacetylase)-containing repressor complex], which seems to be the equivalent of the mammalian NuRD (nucleosome remodelling and deacetylation) complex [21]. Affinity purification of SHREC revealed stable association of Clr1, Clr2, Clr3, Ccq1 and Mit1 subunits. SHREC is a transcriptional gene-silencing effector complex that is recruited to heterochromatic domains where the distinct activities of the Mit1 and Clr3 components makes chromatin refractory to the transcriptional machinery. Interestingly, Ccq1, a telomere maintenance protein, interacts with Clr3 and recruits SHREC at the telomeres [21]. In a separate study, SHREC was found to be associated with Chp2, a HP1 (heterochromatin protein 1) homologue [22]. This suggests that SHREC could exist in multiple distinct forms. The mechanism of action of SHREC at heterochromatic loci is not fully understood. However, there is evidence for two different ways of SHREC recruitment to the heterochromatin loci: (i) The H3K9me (histone H3 methylated at Lys9)-bound HP1 protein targets SHREC; and (ii) SHREC recruitment requires the phosphorylation of HP1 homologues Swi6 and Chp2 by protein kinase CK2 [23]. At heterochromatic loci, SHREC is required for efficient elimination of an NFR (nucleosome-free region) [24] and acts together with the histone chaperone Asf1 to maintain nucleosome occupancy [25], thereby making these genomic regions refractory for transcription. Intriguingly, SHREC is also recruited to euchromatic regions where its function remains to be characterized [21]. Hence one could hypothesize that SHREC utilizes context-dependent chromatin remodelling mechanisms to regulate transcription. The HDAC activity of the NuRD complex on nucleosomal substrates requires ATP hydrolysis [26]. In analogy to this, it would be interesting to see whether the HDAC activity of Clr3 is dependent on the Mit1 ATPase.

Ino80/Swr1

The Ino80 and Swr1 CRCs are multisubunit complexes named after their ATPase subunits. The budding yeast INO80 and SWR1 chromatin remodelling properties have been extensively characterized. However, little is known about their functions in fission yeast. Isolation of the Ino80 complex from fission yeast revealed its association with a unique subunit called Iec1, a YY1 (Yin and Yang 1) mammalian homologue, along with other conserved subunits [27]. Interestingly, this subunit is absent from budding yeast. The fission yeast Ino80 complex functions in nucleosome depletion at target genes involved in phosphate and nucleotide metabolism. It also plays a role in DNA replication and DNA damage response [27]. The S. pombe Swr1 complex functions in the deposition of histone H2A.Z and loss of Swr1 results in mis-regulation of subtelomeric genes and defects in the chromatin structure at centromeres and chromosome segregation [28]. Detailed biochemical and genetic dissection of these complexes are much needed to more completely comprehend their role(s) in gene regulation and chromatin organization.

Etl1

Recently, another SNF2-like helicase called Fft3 (fission yeast Fun thirty), which bears a long insertion within the ATPase domain, was characterized [29]. Fft3 is a member of the Etl1 subfamily and this enzyme is localized to tRNA genes near centromeres and to LTR (long terminal repeat) elements in the subtelomeric regions. Fft3 is required for maintaining sharp boundaries between the centromeric chromatin, subtelomeric chromatin and the surrounding euchromatin regions. Deletion of fft3 results in invasion of active chromatin marks such as acetylated histones and H2A.Z into the centromeric and subtelomeric regions and hence destabilizes the chromatin configurations [29]. It has been shown that Fft3 associates with the nuclear matrix and modulates RanGAP (Ran GTPase-activating protein) functions [30]. Our studies show that Fft3 performs a boundary function by tethering tRNA and LTR elements to the inner nuclear membrane and nuclear pores to regulate higher order chromatin structures (A. Strålfors, B. Steglich, A. Smialowska, O. Khorosjutina, J.-P. Javerzat and K. Ekwall, unpublished work). S. pombe also possesses two more homologues of Fft3, namely Fft1 and Fft2, whose functions remain to be characterized.

Other SNF2 family members

HR (homologous recombination) during DSB repair and successful progression through meiosis is critical for cells to maintain genome integrity. The budding yeast SNF2 ATPase Rad54 is involved in DSB repair by HR [31]. In fission yeast, the Rad54 subfamily contains two homologues called Rhp54 and Rdh54. Although both of these enzymes are essential for meiotic recombination, Rhp54 has been found to be specifically degraded by the ubiquitin-mediated pathway in the G1-phase of the cell cycle. A controlled level of Rhp54 is important for efficient HR of sister chromatids during the late S- and G2-phases [32]. The meiotic DSB repair pathway, resistance to genotoxic reagents and ionizing radiation are significantly compromised in double deletion strains of rhp54 and rdh54 [3234]. Human and budding yeast Rad54 ATPase activity is stimulated by DNA and promotes strand pairing by recruitment and interactions with several other repair proteins [35,36]. S. pombe has other DNA repair pathway proteins such as Rad8, Rhp16 and the Ris1-related proteins Rrp1/Rrp2 which are categorized under the Rad5/16 subfamily of SNF2 enzymes. Mutations in rad8 result in sensitization of cells towards UV and ionizing radiation [37], whereas the rhp16 and rhp26 mutant shows intermediate UV radiation sensitivity and the Rhp16 and Rhp26 proteins are involved in the nucleotide excision repair pathway [38,39]. Deletions of rrp1 and rrp2 along with other genes encoding proteins for DNA repair proteins affect the HR pathway [40]. Although the deletion phenotypes of these genes are known, much work is required to elucidate their molecular mechanism of action in DNA repair processes. A nucleosome remodelling activity of Rad54 and Rad5/16 subfamilies also remains to be demonstrated.

Modulation of chromatin landscape by SNF2 ATPases in S. pombe

The exact organization of chromatin within the nucleus varies among eukaryotic species and hence different factors which modulate the chromatin landscape. Genome-wide nucleosome maps of fission yeast revealed a 154±2 bp nucleosome repeat length with uniformly tightly positioned nucleosomes downstream of the NFR; however, a nucleosome array upstream of the NFR is not so pronounced [41,42]. One evolutionarily conserved mechanism of NFR generation across species is by stretches of nucleosome repelling poly(G) or poly(A) DNA sequence, thereby promoting binding of general regulatory factors such as Sap1 in S. pombe [43]. Interestingly, Givens et al. [42] found that the nucleosome organization around the TSSs can be distinguished on the basis of GO (Gene Ontology) terms. During gene transcription, local changes in the chromatin landscape are needed for transcription machinery to access the underlying DNA sequences. Chromatin alterations such as nucleosome eviction or high turnover of histones are modulated by CRCs at gene promoter and terminator elements. As mentioned above, Hrp1 and Hrp3 not only are involved in regulating histone density at the gene promoters [13], but also regulate the regular spacing of nucleosomes over coding regions [16,18,19]. Such organized nucleosomes over the coding regions are important to occlude cryptic promoter elements from the transcription machinery. To our surprise, we did not find changes in the genome-wide nucleosomal maps upon deletion of snf21, mit1 and swr1 genes [18]. Kristell et al. [44] showed that nitrogen starvation in fission yeast results in a rapid loss of nucleosomes not only at the promoter regions, but also in the coding regions of the induced genes. The SNF2 enzymes required for this change have not been identified. Thorough investigations into the role of SNF2 enzymes and CRCs in histone turnover and nucleosome positioning in vivo are required to obtain a more holistic view of the dynamic regulation of chromatin structure in S. pombe.

Heterochromatin and chromatin remodellers in fission yeast

In fission yeast, heterochromatin exists over DNA repeat elements at pericentromeres, subtelomeres, rDNA (ribosomal DNA) and the silent mating type loci. As in metazoans, a crucial step in S. pombe heterochromatin formation is the methylation of histone H3 Lys9 (H3K9me) by the lysine methyltransferase Clr4, which then serves as a recognition mark for the CD-containing proteins Swi6, Chp1 and Chp2 (HP1 homologues). Clr4 itself also has a CD, which enables it to bind to the methylated lysine residue and possibly enhance methylation of neighbouring lysine residues in a feedforward loop [45].

Swi6 has a CD and a CSD (chromo-shadow domain), which are separated by an unstructured hinge region. Recently, work from the Narlikar laboratory showed that free Swi6 can dimerize with its CSD and oligomerize with its CD in the absence of H3K9me-modified nucleosomes [46]. However, H3K9me, when present, competes for binding with the CD and drives the reaction from an autoinhibited oligomer of Swi6 to a complex of H3K9me with Swi6 dimers (two dimers per nucleosome) in which the two unoccupied CDs protrude out like sticky ends. Since recognition of neighbouring methyl marks depends on the internucleosomal distance, the vacant CDs are thought to bridge nearby methylated nucleosomes and help in propagation of Swi6 on the methylated template [46]. This dimerization mechanism is likely to impose restrictions on the nucleosome repeat length in heterochromatin. Consistent with this notion, the repeat length in H3K9me regions was found to be slightly longer compared with euchromatin [41].

The Swi6 and Chp2 proteins associate with SHREC and the Clr6 HDAC in fission yeast [22,47] Recently, Yamane et al. [25] demonstrated that the histone chaperones Asf1 and HIRA (histone cell cycle defective homologue A) also associate with and spread on Swi6-coated heterochromatin and that Asf1 acts in concert with Clr6 at heterochromatic repeats to suppress antisense transcription. Asf1 also interacts with SHREC to regulate nucleosome occupancy in heterochromatic domains, but surprisingly does not affect the TFIIIC-bound boundary elements.

Experiments by Garcia et al. [24] have highlighted the role of different classes of silencing factors in controlling nucleosome occupancy and periodicity in fission yeast heterochromatin. Using wild-type and mutant strains of clr4, clr3, mit1, swi6 and chp2 in microarrays designed to detect nucleosome position and transcription in conventional heterochromatic and certain euchromatic loci, they report that the nucleosomes are arranged in a less periodic manner in heterochromatin than in euchromatin, an effect that can be compensated for by deletion of clr4. In clr4, there is creation of NFRs inside heterochromatin, which leads to more regularly spaced nucleosomes. Similarly, deletion of the CD proteins Swi6 and Chp2 and catalytically dead mutants of Clr3 and Mit1 of SHREC also lead to the appearance of NFRs and an increase in transcription at certain loci, but not others. A striking example is that of the Mit1 catalytically inactive mutant in which an NFR occurs at the silencing initiation sites of the mat2/3 locus, underlining the fact that nucleosome remodelling by Mit1 is more important at silencing initiators than at the TSS. It is also interesting to note that SHREC antagonizes NFR formation by blocking the recruitment of the RSC remodelling complex, which in budding yeast has been demonstrated earlier to evict nucleosomes and create NFRs [24]. Likewise, different heterochromatic DNA elements have specific combinatorial requirements of the above factors. Among the other chromatin remodellers tested for their ability to (re)organize heterochromatin are the Swi6-interacting proteins Hrp1 and Hrp3. None of them had any effect on nucleosome positioning in heterochromatin, except for hrp1 deletion, which showed an increase in histone occupancy only at the telomeric repeat tel2R [24].

We have demonstrated that Hrp1 is important for maintaining the correct balance of canonical histone H3 and its centromeric variant CENP-A at the centromeric core [12]. In hrp1 cells, there is an increase in H3 levels and acetylated H4 at the centromere associated with defects in chromosome segregation, indicating that Hrp1 may be critical for CENP-A loading and maintenance of centromeric heterochromatic structure [15,48]. In addition, deletion of another remodeller, Fft3, leads to loss of centromeric boundary function and an increase in H3, H2A.Z and acetylated H4 at the centromeres, hinting at a mechanism through which remodellers affect higher-order chromatin structure [29].

Thus heterochromatin formation and maintenance is achieved by: (i) maintaining low levels of acetylated histones and histone variant H2A.Z; (ii) incorporation of the H3K9 methyl mark; (iii) recruitment, spreading and maintenance of HP1 homologues; (iv) transcriptional gene silencing by RNAi mechanisms; (v) low levels of histone turnover; (vi) active heterochromatic boundaries; and (vii) remodelling activity of CRCs to occlude NFRs. As outlined in the present paper, several of these processes involve the action of SNF2 enzymes.

Regulation of histone turnover by CRCs

The dynamic exchange of histones (histone turnover) in a replication-independent manner is not only another mechanism to define gene activity, but also important for genome integrity. The existence of histone-exchange mechanisms and their implications in fission yeast are now unfolding. Genes located within euchromatic regions show rapid histone turnover compared with genes located at the heterochromatic regions [49,50]. Moreover, within gene bodies, histone turnover is higher at the promoter elements than in the coding regions [49]. The lower histone turnover at the heterochromatic loci was implicated due to the activities of HDAC (Clr3), H3K9 methyltransferase (Clr4) and HP1 protein Swi6 [49,50]. However, at this point there is no direct evidence suggesting the role of CRCs in histone dynamics in fission yeast. Hrp1 has been implicated as a facilitator of CENP-A loading at the centromeres [12], whereas SHREC [21] is required for transcriptional gene silencing at all heterochromatic regions. Further investigation is required to understand how chromatin remodelling properties in terms of histone exchange by Hrp1 and SHREC are crucial for CENP-A loading and heterochromatin maintenance respectively.

Concluding remarks

In the present review we have summarized the functions of Snf2 enzymes and different CRCs identified and characterized in the fission yeast S. pombe. Fission yeast is an excellent experimental model in this area because of the low genetic complexity, i.e. there are only 20 different Snf2 enzymes compared with 53 in humans. The well-annotated and small genome (14.1 Mbp), the powerful genetic tools, the well-defined HP1 containing heterochromatin regions and the regional centromeres are all attractive features of S. pombe for research on chromatin remodelling mechanisms. Currently only limited information is available on the functions and mechanisms of Snf2 ATPases in fission yeast, and it is already clear that interesting differences exist compared with budding yeast. Thus further investigations of Snf2 enzymes in S. pombe using both biochemical and genetic approaches in concert with genome-wide methodologies should be rewarding.

The 7th International Fission Yeast Meeting: Pombe 2013: An Independent Meeting/EMBO Conference held at University College London, London, U.K., 24–29 June 2013. Organized and Edited by Jürg Bähler (University College London, U.K.) and Jacqueline Hayles (Cancer Research UK London Research Institute, U.K.).

Abbreviations

     
  • CD

    chromodomain

  •  
  • CENP-A

    centromere protein A

  •  
  • CHD1

    chromodomain, helicase, DNA-binding domain

  •  
  • CRC

    chromatin remodelling complex

  •  
  • CSD

    chromo-shadow domain

  •  
  • DSB

    double-strand break

  •  
  • Fft3

    fission yeast Fun thirty

  •  
  • H3K9me

    histone H3 methylated at Lys9

  •  
  • HDAC

    histone deacetylase

  •  
  • HP1

    heterochromatin protein 1

  •  
  • HR

    homologous recombination

  •  
  • Hrp

    helicase-related protein

  •  
  • LTR

    long terminal repeat

  •  
  • Pol II

    polymerase II

  •  
  • Mit1

    Mi-2-like interacting with Clr three 1

  •  
  • NFR

    nucleosome-free region

  •  
  • NuRD

    nucleosome remodelling and deacetylation

  •  
  • SHREC

    SNF2/HDAC-containing repressor complex

  •  
  • TSS

    transcription start site

Funding

We are supported by the Åke Olsson Foundation for Haematological Research, the Swedish Cancer Foundation, the Swedish Research Council, the Göran Gustafsson Foundation and the Knut and Alice Wallenberg Foundation.

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