During meiosis, each pair of homologous chromosomes typically undergoes at least one crossover (crossover assurance), but these exchanges are strictly limited in number and widely spaced along chromosomes (crossover interference). The molecular basis for this chromosome-wide regulation remains mysterious. A family of meiotic RING finger proteins has been implicated in crossover regulation across eukaryotes. Caenorhabditis elegans expresses four such proteins, of which one (ZHP-3) is known to be required for crossovers. Here we investigate the functions of ZHP-1, ZHP-2, and ZHP-4. We find that all four ZHP proteins, like their homologs in other species, localize to the synaptonemal complex, an unusual, liquid crystalline compartment that assembles between paired homologs. Together they promote accumulation of pro-crossover factors, including ZHP-3 and ZHP-4, at a single recombination intermediate, thereby patterning exchanges along paired chromosomes. These proteins also act at the top of a hierarchical, symmetry-breaking process that enables crossovers to direct accurate chromosome segregation.
Meiosis is conserved across eukaryotes yet varies in the details of its execution. Here we describe a new comparative model system for molecular analysis of meiosis, the nematode Pristionchus pacificus, a distant relative of the widely studied model organism Caenorhabditis elegans. P. pacificus shares many anatomical and other features that facilitate analysis of meiosis in C. elegans. However, while C. elegans has lost the meiosis-specific recombinase Dmc1 and evolved a recombination-independent mechanism to synapse its chromosomes, P. pacificus expresses both DMC-1 and RAD-51. We find that SPO-11 and DMC-1 are required for stable homolog pairing, synapsis, and crossover formation, while RAD-51 is dispensable for these key meiotic processes. RAD-51 and DMC-1 localize sequentially to chromosomes during meiotic prophase and show nonoverlapping functions. We also present a new genetic map for P. pacificus that reveals a crossover landscape very similar to that of C. elegans, despite marked divergence in the regulation of synapsis and crossing-over between these lineages.
During the transition from pluripotency to a lineage-committed state, chromatin undergoes large-scale changes in structure, involving covalent modification of histone tails, use of histone variants, and gene position changes with respect to the nuclear periphery. Here, using high-resolution microscopy and quantitative image analysis, we surveyed a panel of histone modifications for changes in nuclear peripheral enrichment during differentiation of human embryonic stem cells to a trophoblast-like lineage. We found two dynamic modifications at the nuclear periphery: acetylation of histone H2A.Z (H2A.Zac), and dimethylation of histone H3 at lysine 9 (H3K9me2). We demonstrate successive peripheral enrichment of these markers, with H2A.Zac followed by H3K9me2, over the course of 4 days. We find that H3K9me2 increases concomitantly with but independently of Lamin A, since deletion of Lamin A did not affect H3K9me2 enrichment. We further show that inhibition of histone deacetylases causes persistent and increased H2A.Z acetylation at the periphery, delayed H3K9me2 enrichment, and failure to differentiate. Our results show a concerted change in the nature of peripheral chromatin occurs upon differentiation into the trophoblast state.
1The goal of meiosis is to produce haploid gametes from diploid progenitor cells. While meiosis was likely 2 present in the last eukaryotic common ancestor (LECA), diversity in meiotic mechanisms has long been 3 observed among sexually reproducing eukaryotes. Here we describe a new, comparative model system for 4 molecular analysis of meiosis, the nematode Pristionchus pacificus, a distant relative of the widely 5 studied model organism Caenorhabditis elegans. Despite superficial similarities in germline organization 6 and meiotic progression between P. pacificus and C. elegans, we identify fundamental differences in the 7 molecular mechanisms underlying homolog pairing, synapsis, and crossover regulation. Whereas C. 8 elegans has lost the meiosis-specific recombinase Dmc1, P. pacificus expresses both DMC-1 and RAD-9 51, which localize sequentially to meiotic chromosomes during prophase. We find that Ppa-spo-11 and 10Ppa-dmc-1 are required for stable homolog pairing, synapsis, and crossover formation, while Ppa-rad-51 11 is dispensable for these key processes during early prophase and plays a supporting role in meiotic 12 double-strand break repair. Additionally, we show that elevated crossover recombination in P. pacificus 13 likely arises through a Class II pathway normally inactive in C. elegans, shedding light on crossover 14 control and the evolution of recombination rates. 15 16 17 model Mus musculus (Bishop et al., 1992;Couteau et al., 1999;Grelon, 2001;Pittman et al., 1998; 43 Rockmill et al., 1995;Yoshida et al., 1998). 44In contrast, recombination-independent mechanisms of pairing and synapsis have been 45 characterized in other prominent model systems, including the dipteran Drosophila melanogaster and the 46 nematode Caenorhabditis elegans. While recombination is essential for successful execution of meiosis 47 elegans, P. pacificus is an androdioecious species, characterized by a population of mostly self-fertilizing 61 hermaphrodites (XX) and a low frequency of males (XO) (Sommer et al., 1996). Like C. elegans, P. 62 pacificus has a short life cycle of 3.5 days, produces large broods of about 200 progeny by self-63 fertilization, and is easily cultured in the lab (Hong and Sommer, 2006). Although C. elegans and P. 64 pacificus diverged an estimated 200-300 million years ago (Pires-daSilva, 2004), they share the same 65 number of chromosomes (2n=12) and, with the exception of one major chromosomal translocation, 66 macrosynteny is maintained between the two species (Dieterich et al., 2008; Rödelsperger et al., 2017). P. 67 pacificus has been established as a model for comparative studies in development, evolution and ecology 68 4 (Sommer, 2015). Recent improvements in the genome assembly (Rödelsperger et al., 2017) and advances 69 in genome editing (Lo et al., 2013; Namai and Sugimoto, 2018; Witte et al., 2015) have facilitated 70 investigation of cell biological processes at a more mechanistic level. 71 In addition to these general features that make P. pacificus a tractable model system, previou...
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