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Centromere Repositioning Causes Inversion of Meiosis and Generates a Reproductive Barrier

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Centromere Repositioning Causes Inversion of Meiosis and Generates a Reproductive Barrier Centromere repositioning causes inversion of meiosis and generates a reproductive barrier Min Lua and Xiangwei Hea,1 aMinistry of Education Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, 310058 Hangzhou, Zhejiang, China Edited by J. Richard McIntosh, University of Colorado, Boulder, CO, and approved September 20, 2019 (received for review July 10, 2019) The chromosomal position of each centromere is determined postulated that a neocentromere may seed the formation of an epigenetically and is highly stable, whereas incremental cases ENC at a site devoid of satellite DNA, which is then matured have supported the occurrence of centromere repositioning on an through acquisition of repetitive DNA. ENCs and neocentromeres evolutionary time scale (evolutionary new centromeres, ENCs), are considered as two sides of the same coin, manifestations of the which is thought to be important in speciation. The mechanisms same biological phenomenon at drastically different time scales underlying the high stability of centromeres and its functional and population sizes (7). Hence, understanding centromere repo- significance largely remain an enigma. Here, in the fission yeast sitioning may provide mechanistic insights into ENC emergence Schizosaccharomyces pombe, we identify a feedback mechanism: and progression. The kinetochore, whose assembly is guided by the centromere, in CENP-A–containing chromatin directly recruits specific com- turn, enforces centromere stability. Upon going through meiosis, ponents of the kinetochore, called the constitutive centromere- specific inner kinetochore mutations induce centromere reposi- associated network. The kinetochore is a proteinaceous ma- tioning—inactivation of the original centromere and formation chinery comprised of inner and outer parts, each compassing of a new centromere elsewhere—in 1 of the 3 chromosomes at several subcomplexes. The inner kinetochore is proximal to or in random. Repositioned centromeres reside asymmetrically in the direct contact with the CENP-A nucleosomes, linking the cen- pericentromeric regions and cells carrying them are competent in tromere to the outer kinetochore, which in turn physically binds mitosis and homozygotic meiosis. However, when cells carrying a the spindle microtubules (8). Mutations in the N-terminal tail of repositioned centromere are crossed with those carrying the orig- CENP-A reduce the centromeric localization of the inner ki- CELL BIOLOGY inal centromere, the progeny suffer severe lethality due to defects netochore component CENP-T and cause centromere inactivation in meiotic chromosome segregation. Thus, repositioned centro- (9). Previous studies, including ours (10), have shown that kinet- meres constitute a reproductive barrier that could initiate genetic ochore components may contribute to the stability of the centro- divergence between 2 populations with mismatched centromeres, meric chromatin organization pattern. Certain inner kinetochore documenting a functional role of ENCs in speciation. Surprisingly, components (e.g., Mis6 and Cnp3 in S. pombe;CENP-Cand homozygotic repositioned centromeres tend to undergo meiosis in CENP-N in vertebrates) are required for maintaining proper an inverted order—that is, sister chromatids segregate first, and levels of CENP-A nucleosomes in centromeres (11–14). More- homologous chromosomes separate second—whereas the original over, partial dysfunction of the kinetochore (e.g., mis6-302, mis12- centromeres on other chromosomes in the same cell undergo mei- 537,andams2Δ) facilitates centromere inactivation and rescues osis in the canonical order, revealing hidden flexibility in the per- the high rates of lethality causedbyanengineereddicentric ceived rigid process of meiosis. Significance inner kinetochore | CENP-T-W-S-X complex | centromere repositioning | reproductive barrier | inverted meiosis Mutations in inner kinetochore components induce centromere repositioning without alteration in the centromeric DNA sequence, entromeres dictate the sites on chromosomes for kineto- revealing a feedback mechanism underlying the high epigenetic Cchore assembly and provide the foundation for spindle stability of the centromere. This also provides a desirable experi- microtubule attachment to assure the faithful chromosome mental system to explore the functional significance of centromere transmission during mitosis and meiosis (1, 2). For most eukary- positioning in meiosis. We discovered that in a heterozygotic otes, including humans and fission yeast, centromeres span a meiosis, a repositioned centromere generates a reproductive bar- specific region—tens of kilobases in the fission yeast Schizo- rier, suggesting a functional role of evolutionary new centromeres saccharomyces pombe, up to megabases in mammals and plants— in speciation; furthermore, in a homozygotic meiosis, chromo- of the chromatin, which are called monocentromeres. The posi- somes carrying repositioned centromeres frequently undergo the 2 tion of the centromere on each chromosome is determined stages of meiotic segregation in an inverted order, demonstrating epigenetically by an evolutionarily conserved histone H3 variant, high flexibility in the meiotic process. CENP-A (3). While the underlying centromeric DNA sequences are usually highly repetitive (called satellite or alphoid DNA), they Author contributions: M.L. conceived the project; M.L. and X.H. designed research; M.L. performed research; M.L. analyzed data and prepared figures; and M.L. and X.H. wrote diverge dramatically among species. Furthermore, the underlying the paper. DNA sequence does not determine the site of a centromere. The The authors declare no competing interest. formation of a functional neocentromere, defined by a new cen- This article is a PNAS Direct Submission. tromere formed on an ectopic site other than that of the original This open access article is distributed under Creative Commons Attribution-NonCommercial- centromere, is independent of the DNA sequence (4). NoDerivatives License 4.0 (CC BY-NC-ND). Centromere positioning on each chromosome is remarkably Data deposition: The data reported in this paper have been deposited in the Gene Ex- stable in all eukaryotes, although centromere repositioning due pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. to neocentromere formation without alteration in the chromo- GSE118016). somal marker order does occur sporadically in contemporary 1To whom correspondence may be addressed. Email: [email protected]. populations (e.g., 8 cases have been reported in humans) (5) and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. among related species (such as primates) on the evolutionary 1073/pnas.1911745116/-/DCSupplemental. time scale (i.e., evolutionary new centromeres, ENCs) (6). It is www.pnas.org/cgi/doi/10.1073/pnas.1911745116 PNAS Latest Articles | 1of12 Downloaded by guest on September 24, 2021 chromosome in fission yeast (15). In general, these data suggest displayed a similar heterochromatin spreading at the nonpermissive functional cross-talk between the centromere and the kinetochore. and permissive temperatures, indicating that centromeric chromatin Centromere–kinetochore–microtubule attachment is crucial organization is already impaired in cells under the viable condition. for accurate chromosome segregation in mitosis as well as mei- mhf2Δ (mammalian CENP-X homolog) exhibited complete het- osis. Meiosis occurs in eukaryotes that generate germ cells for erochromatin occupancy in one centromere (cen1)butnormalperi- sexual reproduction. Canonical meiosis involves 2 sequential centromeric distribution in the other two (cen2 and cen3)(Fig.1A nuclear divisions (meiosis I and meiosis II) following 1 round of and SI Appendix,Fig.S1A). The island-shape ChIP-seq signals de- DNA replication (16). The order of the segregation events is tected on cnt3 in mhf2Δ are most likely caused by an artifact in highly conserved. It is characterized by homologous chromosome informatics data processing as the border of the small island aligns pair separation during the first “reductional” division (meiosis I) precisely with the identical sequence in cnt1 and cnt3,whichis followed by sister chromatids segregation during the second biochemically highly unlikely (also see below). In a double-mutant “equational” division (meiosis II). To accomplish faithful chro- cnp3Δfta6Δ strain, derived from genetic crossings, we found that mosome segregation in such a distinct manner, sister kineto- cen2 was completely covered by heterochromatin (Fig. 1A and SI chores must initially establish connection with only 1 pole of the Appendix,Fig.S1A), suggesting that perturbations to centromeric spindle in meiosis I (called “mono-orientation”) so that they are chromatin by cnp3Δ and fta6Δ cumulatively led to centromere cosegregated, whereas in meiosis II, they must establish biori- inactivation. entation with the 2 poles of the spindle in order to be segre- Anti-Cnp1 ChIP-seq detected no significant Cnp1 signal at gated equally. In addition, crossover and sequential resolution of centromeric cores occupied by heterochromatin but prominent chromosome cohesion along chromosome arms in meiosis I and at levels of Cnp1 at the other two in both mhf2Δ and cnp3Δfta6Δ centromeres in meiosis II are also necessary to fulfill the re- (Fig. 1B), confirming that only the original cen1 or cen2 was quirements
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