A Heterochromatin Domain Forms Gradually at a New Telomere and Is Highly Dynamic at Stable

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A Heterochromatin Domain Forms Gradually at a New Telomere and Is Highly Dynamic at Stable bioRxiv preprint doi: https://doi.org/10.1101/211565; this version posted November 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 A heterochromatin domain forms gradually at a new telomere and is highly dynamic at stable 2 telomeres 3 4 Jinyu Wang a,c*, Jessica R Eisenstatt b,c†, Julien Audryc, Kristen Corneliusd, Matthew Shaughnessyc, 5 Kathleen L Berknerc, Kurt W Rungea,b,c# 6 7 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 8 USAa; Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USAb; 9 Departments of Immunology and Molecular Genetics, Lerner Research Institute, Cleveland Clinic 10 Foundation, Cleveland, OH, USAc; Department of Molecular Genetics, The Ohio State University, 11 Columbus, OH, USAd 12 13 Running Head: Formation and stability of heterochromatin domains 14 15 #Address correspondence to Kurt W Runge, rungek@ccf.org. 16 *Present address: Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, 17 MA, USA 18 †Present address: Genetics Branch, National Cancer Institute, National Institutes of Health, 19 Bethesda, MD, USA 20 J.W and J.R.E contributed equally to this work. 21 22 Word count for Materials and Methods: 1801 words 23 Word count for Introduction, Results and Discussion: 4528 words 24 Page 1 of 45 bioRxiv preprint doi: https://doi.org/10.1101/211565; this version posted November 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 25 Abstract 26 Heterochromatin domains play important roles in chromosome biology, organismal development 27 and aging. In the fission yeast Schizosaccharomyces pombe and metazoans, heterochromatin is marked 28 by histone H3 lysine 9 dimethylation. While factors required for heterochromatin have been identified, 29 the dynamics of heterochromatin formation are poorly understood. Telomeres convert adjacent 30 chromatin into heterochromatin. To form a new heterochromatic region in S. pombe, an inducible DNA 31 double-strand break (DSB) was engineered next to 48 bp of telomere repeats in euchromatin, which 32 caused formation of new telomere and gradual spreading of heterochromatin. However, spreading was 33 highly dynamic even after the telomere had reached its stable length. The system also revealed the 34 presence of repeats located at the boundaries of euchromatin and heterochromatin that are oriented to 35 allow the efficient healing of a euchromatic DSB to cap the chromosome end with a new telomere. 36 Telomere formation in S. pombe therefore reveals novel aspects of heterochromatin dynamics and the 37 presence of failsafe mechanisms to repair subtelomeric breaks, with implications for similar processes in 38 metazoan genomes. 39 Page 2 of 45 bioRxiv preprint doi: https://doi.org/10.1101/211565; this version posted November 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 40 Introduction 41 A central question in eukaryotic biology is the establishment and maintenance of chromatin 42 domains, i.e. regions of nucleosomal DNA where the histone composition and spectrum of post- 43 translational modifications are similar. As embryonic cells differentiate, cell type-specific gene 44 expression is established in part by the establishment and maintenance of chromatin domains (e.g. 45 changes in the globin locus in hematopoietic cells, X-chromosome inactivation in females mammals (1, 46 2)). Chromatin domain reorganization also occurs during tumorigenesis as cells transform into rapidly 47 growing cancers (3). Heterochromatin domains, marked in part by nucleosomes with di- and tri- 48 methylation of lysine 9 of histone H3 (H3K9me2 or 3), have been intensely studied for their role in 49 chromosome biology. Heterochromatin domains are known for silencing gene expression (4), and can 50 be induced during mammalian cell senescence and aging to form senescence-associated heterochromatin 51 foci containing H3K9me2 (5–7). Heterochromatin also plays an important role at centromeres, the 52 chromosomal structure required for chromosome segregation at mitosis, as centromeric chromatin is 53 flanked by heterochromatin domains that are required for complete function (8–11). While many of the 54 factors required to maintain heterochromatin have been identified, the dynamics of how heterochromatin 55 domains assemble and disassemble have remained long-standing, major questions that are only now 56 being investigated (12–14). 57 Telomeres, the physical ends of chromosomes, are a second chromosomal structure bordered by 58 heterochromatin. In yeast, humans and many other eukaryotes, telomeres consist of simple DNA 59 repeats bound by specific proteins. These repeats and their associated proteins provide the first 60 discovered essential function of telomeres: “that of sealing the end of the chromosome” (15), and 61 distinguishing it from a Double-Strand Break (DSB)(15, 16). The second essential function is to replace 62 sequences lost due to incomplete replication, which is accomplished by repeat addition via telomerase 63 ((17, 18), reviewed in (19)). Telomeres also alter the adjacent nucleosomal chromatin to silence the 64 expression of nearby genes (20, 21). However, as mutations that eliminate silencing do not cause Page 3 of 45 bioRxiv preprint doi: https://doi.org/10.1101/211565; this version posted November 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 65 telomeres to behave as DSBs (20, 22, 23), the essential functions of telomeres act independently of gene 66 silencing. Heterochromatic gene silencing is associated with the presence of H3K9me2 in humans, flies 67 and the fission yeast Schizosaccharomyces pombe (24), and S. pombe telomere-associated chromatin has 68 the H3K9me2 modification (22, 23, 25). Thus, S. pombe telomeres provide an ideal model system to 69 study heterochromatin and heterochromatin dynamics. 70 A major difficulty that impedes the investigation of heterochromatin domain dynamics is the 71 large amount of time between the initiation of domain formation and its analysis. Telomeres have been 72 formed in S. pombe by integrating in vitro constructed telomeric DNA into genomic sites in vivo, but 30 73 population doublings (PDs) or more must pass between the formation of the new telomere and the 74 production of enough cells for chromatin and phenotypic analysis (21). Similar approaches requiring 75 many PDs have followed heterochromatin formation at centromeres and other loci by introducing wild 76 type genes into mutants defective for heterochromatin assembly (26–29). This approach also converts a 77 mutant cell to a wild type one, so the levels of cellular chromatin proteins during domain formation are 78 initially different than wild type cells. Consequently, the kinetics of heterochromatin formation and how 79 the H3K9me2 modification spreads from the initiating site into the surrounding chromatin is largely 80 unknown in either wild type or mutant cells. One hypothesis would be that spreading occurs 81 immediately after the initiating site is created and quickly establishes the final heterochromatin domain 82 within one or two generations (as with Sir protein spreading in Saccharomyces cerevisiae (30–32)). 83 Alternatively, the formation of the initiation site, e.g. a functional telomere, may allow spreading over 84 many cell divisions, with the size of the heterochromatin domain gradually increasing over time to form 85 the final state (as suggested for several histone modifications in (30) and in S. pombe in (14)). 86 An inducible telomere formation system would provide an approach to study the kinetics of 87 heterochromatin formation in wild type cells. Such systems contain a selectable marker followed by an 88 internal tract of telomere repeats and a unique restriction site or cut site not present elsewhere in the 89 genome. By placing the restriction enzyme or endonuclease gene under the control of a rapidly Page 4 of 45 bioRxiv preprint doi: https://doi.org/10.1101/211565; this version posted November 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 90 inducible promoter, one can induce a DSB in a large population of cells to expose the telomere repeats 91 at the new chromosome end (33). In S. cerevisiae and S. pombe, a DSB in the middle of a chromosome 92 normally leads to DNA degradation and growth inhibition (33–35)(Figure 1A). In contrast, a telomere 93 formation system in S. cerevisiae and mammalian cells has shown that a DSB which exposes telomere 94 repeats is immediately converted into a short, functional telomere that is not degraded (33, 36– 95 38)(Figure 1B). The S. cerevisiae telomere formation system has yielded important insights into the 96 roles of telomerase, telomere binding proteins, DNA polymerases and DNA damage proteins in 97 telomere elongation (reviewed in (39)). However, S. cerevisiae lacks the H3K9me2 modification 98 system, and so its use in modeling the kinetics of heterochromatin spreading that occurs in metazoans is 99 limited. 100 S. pombe is a useful model for studying the H3K9me2 heterochromatin system (40), but a 101 telomere formation system was previously not feasible owing to the lack of a method to rapidly induce a 102 DSB.
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