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Crossovers from B6xCAST F1 PRDM9-Humanized/CAST testes

ABSTRACT: We report 2,649 crossover breakpoints identified by single-cell DNA sequencing of 217 sperm in a B6xCAST F1 mouse, which is heterozygous at Prdm9, with one wild-type CAST allele and one allele found in human populations (bred from a genetically engineered mother, Davies et al Nature 2012). Separately, we have reported testis DMC1 enrichment in the same mouse (GSE124991). We also infer H3K4me3 intensities at DMC1 hotspots, based on the raw H3K4me3 ChIP-seq data published under GSE119727 (Li et al). We identify several factors, including PRDM9 binding on the repair-template homologue, telomere proximity and local GC-content, that affect the probability that a DSB is repaired as a crossover. We further show that these factors also influence the time it takes for the site of a DSB to find and engage its homologue, with rapidly-engaging sites being more likely to be repaired as crossovers.

ORGANISM(S): Mus musculus

PROVIDER: GSE125326 | GEO | 2019/03/18

REPOSITORIES: GEO

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DMC1 ChIP-seq from B6xCAST F1 PRDM9-Humanized/CAST testes

Project description:We report testis DMC1 enrichment at DSB (Double-Strand Break) hotspots in a B6xCAST F1 mouse, which is heterozygous at Prdm9, with one wild-type CAST allele and one allele found in human populations (bred from genetically engineered mother, Davies et al Nature 2012). We also report H3K4me3 intensities at these hotspots, based on the raw data published under GSE119727 (Li et al). Separately, we have reported 2,649 crossover locations identified by single-cell DNA sequencing of 217 sperm from the same hybrid mouse. We identify several factors, including PRDM9 binding on the repair-template homologue, telomere proximity and local GC-content, that affect the probability that a DSB is repaired as a crossover. We further show that these factors also influence the time it takes for the site of a DSB to find and engage its homologue, with rapidly-engaging sites being more likely to be repaired as crossovers.

2019-03-18 | GSE124991 | GEO

Humanized PRDM9 Mouse Testis H3K4me3 and DMC1 ChIP-seq

Project description:We report testis H3K4me3 and DMC1 enrichment at DSB hotspots in various mice to examine differences between infertile hybrid mice and mice that have been humanized at PRDM9, which have rescued fertility. We find that infertile mice have an excess of "asymmetric" DSB hotspots, where both H3K4me3 and DMC1 reads tend to originate from only one homologue. At these hotspots, we see an excess of DMC1 relative to H3K4me3, consistent with delayed DSB repair at these sites. See Davies et al. Nature 2016 for a complete summary.

2016-02-02 | GSE73833 | GEO

H3K4me3 ChIP-seq from B6CASTF1-PRDM9 Humanized/CAST testes

Project description:We report testis H3K4me3 enrichment in an F1 male from a C57BL/6J (B6) x CAST/Eij (CAST) cross (B6 mother, CAST father). This mouse is heterozygous at PRDM9 for a humanized allele (Davies et al. Nature 2016) and the CAST allele. After filtering of promoter H3K4me3 regions, these data serve as a measure of PRDM9 binding enrichment on each homologue. We found that both crossovers and non-crossovers (observed by sequencing F2/F4/F5 genomic DNA) are depleted at "asymmetric" Double-Strand Break hotspots where PRDM9 primarily binds only one of the two homologues. This proves that PRDM9 plays an important role in promoting inter-homologue interactions and can explain why increasing PRDM9 binding asymmetry predicts hybrid infertility. See Li, Bitoun, Altemose et al. 2018 (pending) for a complete summary.

2018-09-28 | GSE119727 | GEO

Refined spatial temporal epigenomic profiling reveals intrinsic connection between PRDM9-mediated H3K4me3 and the fate of double-stranded breaks

Project description:Meiotic recombination is initiated by the formation of double-strand breaks (DSBs), which are repaired as either crossovers (COs) or noncrossovers (NCOs). In most mammals, PRDM9-mediated H3K4me3 controls the nonrandom distribution of DSBs; however, both the timing and mechanism of DSB fate control remain largely undetermined. Here, we generated comprehensive epigenomic profiles of synchronized mouse spermatogenic cells during meiotic prophase I, revealing spatiotemporal and functional relationships between epigenetic factors and meiotic recombination. We find that PRDM9-mediated H3K4me3 at DSB hotspots, coinciding with H3K27ac and H3K36me3, is intimately connected with the fate of the DSB. Our data suggest that the fate decision is likely made at the time of DSB formation: earlier formed DSBs occupy more open chromatins and are much more competent to proceed to a CO fate. Our work highlights an intrinsic connection between PRDM9-mediated H3K4me3 and the fate decision of DSBs, and provides new insight into the control of CO homeostasis.

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RPA and RAD51 ChIP-seq from B6 and B6xCAST F1 PRDM9-Humanized/CAST mouse testes

Project description:Meiotic recombination is initiated by programmed DNA double-strand breaks (DSBs) and proceeds via binding of RPA, RAD51 and DMC1 to single-stranded DNA (ssDNA) substrates created after the formation of DSBs. Here, we report high-resolution in vivo maps of RPA and RAD51 binding in meiosis, mapping their binding locations and lifespans in a B6 and a genetically modified B6xCAST F1 mouse. We ascribe signals separately to the individual homologous chromosomes in the hybrid mouse, thereby separating the signal of binding to the chromosome where DSBs occurred and the chromosome that was used as template for repair. Together with super-resolution microscopy and DMC1 binding maps, we show that DMC1 and RAD51 have distinct spatial localization on ssDNA: whereas DMC1 binds near the break-site, RAD51 binds away from it. We characterize the D-loop, a critical intermediate bound by RPA, in vivo. These data show that DMC1, not RAD51, performs strand exchange in mammalian meiosis. We find that the localisation of D-loop intermediates is similar in crossover and non-crossover pathways, with a longer lifespan for crossover-destined intermediates. These findings answer long-standing questions about the molecular intermediates of recombination.

2020-06-30 | GSE143582 | GEO

Identification of PRDM9 partners

Project description:PRDM9 specifies the sites of meiotic DNA double strand break that initiate meiotic recombination in mice and humans. PRDM9 is known to bind to specific DNA sequences with its DNA binding domain, to induce H3K4me3 and H3K36me3 to adjacent nucleosomes through its methyltransferase activity, and to recruit or activate the meiotic DSB machinery. To understand how PRDM9 executes these various steps, we set up to identify its partners. This was performed by a proteomic approach where protein extracts from mouse testis were immunoprecipitated with anti-PRDM9 antibody for mass spectrometry analysis.

2020-12-03 | PXD017337 | Pride

Genome-wide map of H3K4me3 and PRDM9-binding in 12 day post-partum mouse spermatocytes

Project description:PRDM9, a histone methyltransferase, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we compared activity of the Prdm9Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced. Comparing these two strains, we find that haplotype differences at hotspots leads to qualitative and quantitative changes in PRDM9 binding and activity. Most variants affecting PRDM9Cst binding arose and were fixed in M.m castaneus, suppressing hotspot activity. Furthermore, M.m castaneus x M.m domesticus F1 hybrids exhibit novel hotspots, representing sites of historic evolutionary erosion. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion. Identify position of meiotic H3K4me3 from various sub-species of mice and F1 hybrids from crosses between subspecies. In addition, perform ChIP-seq analysis on the meiosis-specific methyltransferase PRDM9.

2015-01-13 | E-GEOD-60906 | biostudies-arrayexpress

Genome-wide map of H3K4me3 in 12 day post-partum mouse spermatocytes

Project description:Here we characterize the genome-wide chromatin modification by PRDM9, a histone H3 lysine 4 methyltransferase. In order to detect PRDM9 binding sites we created coisogenic strains of mice differing only in the zinc finger array of PRDM9. One strain is C57BL/6J, which carries the Prdm9Dom2 allele, the other strain was created using genomic replacement and named B6.PRDM9Cst (also called KI), and contains the Prdm9Cst allele originally found in CAST/EiJ mice. Many H3K4me3 positions are common between strains and represent other methyltransferase activity (such as promoters), sites that are unique to one mouse strain likely represent the binding position of that allele of PRDM9. Identify PRDM9-dependent H3K4me3 sites by comparing modified chromatin from mice coisogenic for Prdm9.

2014-02-24 | E-GEOD-52628 | biostudies-arrayexpress

Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

Project description:The locations of mammalian recombination hotspots are determined by PRDM9, a zinc finger histone methyltransferase that locally trimethylates histone H3 at residues K4 and K36. Here we report Prdm9-EP, a glu365pro mutation that severely reduces catalytic activity in vivo. This mutation causes sterility with complete meiotic arrest in homozygous males, while homozygous females are able to produce live offspring in natural matings. These H3K4me3 ChIP-seq data from Prdm9-EP homozygous spermatocytes show the extent to which H3K4 methyltransferase activity is compromised by this mutation, while the DMC1 ChIP-seq data show its effect on meiotic double-strand breaks in spermatocytes. For comparison, we mapped previously reported H3K4me3 ChIP-seq data from wild-type C57BL/6J spermatocytes (GSE52628) to mm10, merging the two biological replicates (SRX381465 and SRX381466) before mapping, and proceeding with processing. We did the same with published DMC1 ChIP-seq data, merging three previously reported DMC1 ChIP-seq biological replicates, isolated from wild-type C57BL/6N males (GSE112110; SRX3825301, SRX3825302, and SRX3825303). Processed data files are presented here.

2020-10-23 | GSE144144 | GEO

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Project description:The programmed formation of hundreds DNA double strand breaks (DSBs) is essential for proper meiosis and fertility. In mice and humans, the location of these breaks is determined by the meiosis-specific protein PRDM9, through the DNA binding specificity of its zinc finger domain. PRDM9 also has methyltransferase activity. Here, we show that this activity is required for H3K4me3 and H3K36me3 deposition and for DSB formation at PRDM9 binding sites. By analyzing mice that express two PRDM9 variants with distinct DNA binding specificities, we reveal severalthe basic principles of PRDM9-dependent DSB site determination, in which an excess of sites are designated through PRDM9 binding and subsequent histone methylation, from which a subset are selected for DSB formation.

2018-02-09 | GSE108953 | GEO

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