Refined spatial temporal epigenomic profiling reveals intrinsic connection between PRDM9-mediated H3K4me3 and the fate of double-stranded breaks
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ABSTRACT:
PROVIDER: PRJNA548107 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11848343.fastq.gz | Fastqsanger.gz | |||
| SRR11848344.fastq.gz | Fastqsanger.gz | |||
| SRR11848345.fastq.gz | Fastqsanger.gz | |||
| SRR11848346.fastq.gz | Fastqsanger.gz | |||
| SRR11848347.fastq.gz | Fastqsanger.gz |
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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.
2020-02-12 | GSE132446 | GEO
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.
| S-EPMC7054334 | biostudies-literature
Project description:Meiotic crossovers result from homology-directed repair of double strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates, DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9), which subsequently catalyzes trimethylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9 and co-evolved with Prdm9 in vertebrates, as an essential meiotic recombination factor required for efficient synapsis and repair of PRDM9-dependent DSBs. In sum, our results indicate that the evolution of dual histone methylation reader/writer system involving Prdm9 and Zcwpw1 facilitated a shift in genetic recombination away from a static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9
2020-05-12 | GSE139289 | GEO
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
Project description:PRDM9 is a histone methyltransferase expressed in meiotic germ cells that determines the location of genetic recombination hotspots through binding of its allele-specific DNA binding domain. Here we characterize the genome-wide chromatin modification for two human PRDM9 alleles (A and C) in human cell lines. HEK293 cells were transfected with both alleles and an empty vector control. Resulting chromatin was subjected to H3K4me3 ChIP followed by high-throughput sequencing. We find that different PRDM9 allele largely modified chromatin in entirely different genomic regions in somatic cells determined by the protein's zinc-finger DNA binding domains. Many of the allele-specific peaks overlap sites of meiotic double-strand breaks found in vivo in human germ cells suggesting that transient expression of PRDM9 in somatic cells can reflect binding in vivo. Identify PRDM9-dependent H3K4me3 sites by comparing modified chromatin after expression of different human PRDM9 alleles in HEK293 cells.
2015-09-21 | E-GEOD-67673 | biostudies-arrayexpress
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
Project description:Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9-binding sites. The molecular steps occurring from PRDM9 binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.
2020-11-19 | GSE145768 | GEO
Project description:The PRDM9 protein determines sites of meiotic recombination in humans by directing meiotic DNA double strand breaks to specific loci. Targeting specificity is encoded by a long array of C2H2 zinc fingers that binds to DNA. This zinc finger array is hypervariable, resulting in innumerable alleles, each with a potentially different DNA binding preference. Assessment of PRDM9 diversity is important for understanding the complexity of human population genetics, inheritance linkage patterns, and the predisposition to genetic disease. Due to the repetitive nature of the PRDM9 zinc finger array, large-scale sequencing of human PRDM9 is challenging. We therefore developed a long-read sequencing strategy to infer the diploid PRDM9 zinc finger array genotype in a high-throughput manner. From an unbiased study of PRDM9 allelic diversity in 716 individuals from 7 human populations, we detected 70 high-confidence PRDM9 alleles. Several alleles differ in frequency among human populations and 33 alleles had not been identified by previous studies, which were heavily biased to European populations. PRDM9 alleles are distinguished by their DNA binding site preferences and fall into two major categories related to the most common PRDM9-A and PRDM9-C alleles. We also find that inter-conversion between allele types is likely rare. By mapping meiotic DSBs in testis, we find that small variations in PRDM9 can substantially alter the meiotic recombination landscape, demonstrating that minor PRDM9 variants may play an under-appreciated role in shaping patterns of human recombination. In summary, our data greatly expands our knowledge of PRDM9 diversity in humans.
2021-10-26 | GSE166483 | GEO
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
Project description:In mouse and human meiosis, DNA double strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence specific DNA binding domain of the PRDM9 histone methyl transferase. Here we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a non-canonical recruitment of PRDM9 to sites which are devoid of both, recombination activity and the PRDM9-binding consensus motif. These sites include transcription promoters, where PRDM9 is recruited in a DSB-dependent manner. Another subset of non-canonical sites also reveals DSB-independent interactions between PRDM9 and genomic sites, which include binding sites for the insulator protein CTCF. We propose that these DSB-independent sites result from interactions between hotspot bound PRDM9 and genomic sequences located on the chromosome axis.
2017-02-08 | GSE93955 | GEO