HELLS and PRDM9 from a pioneer complex to open chromatin at meiotic recombination hotspots
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ABSTRACT:
PROVIDER: PRJNA560498 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9986120_1.fastq.gz | Fastqsanger.gz | |||
| SRR9986120_2.fastq.gz | Fastqsanger.gz | |||
| SRR9986130.fastq.gz | Fastqsanger.gz | |||
| SRR9986140.fastq.gz | Fastqsanger.gz | |||
| SRR9986150.fastq.gz | Fastqsanger.gz |
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Project description:Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we identify that the DNA-binding protein PRDM9 and chromatin remodeler HELLS function together to open chromatin at hotspots providing access to the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited by PRDM9, and is necessary for both histone modification and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment to open chromatin in preparation for proper placement and repair of DSBs.
2019-12-17 | GSE135896 | GEO
Project description:Mammalian genetic recombination is concentrated at hotspots, specialized 1-2 Kb sites separated by long stretches of DNA lacking recombination. Mammalian hotspot locations depend on PRDM9, a zinc finger protein that binds at hotspots and uses its SET domain to locally trimethylate histone H3K4. Here we find that PRDM9 also locally trimethylates H3K36 at hotspots. Using ChIP-seq and immunoprecipitation data for H3K36me3 in murine spermatocytes, we show that H3K4me3 and H3K36me3 coincide only at hotspots in germ cells, and that this H3K4me3/H3K36me3-double-positive signature is almost entirely dependent on PRDM9. We performed ChIP-seq with an antibody against H3K36me3, using chromatin extracted from murine spermatocytes, and compared it to previously generated ChIP-seq data for H3K4me3 in the same cell type. ---------------------------------- This dataset represents the H3K36 component only
2016-06-30 | E-GEOD-76416 | biostudies-arrayexpress
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:Mammalian genetic recombination is concentrated at hotspots, specialized 1-2 Kb sites separated by long stretches of DNA lacking recombination. Mammalian hotspot locations depend on PRDM9, a zinc finger protein that binds at hotspots and uses its SET domain to locally trimethylate histone H3K4. Here we find that PRDM9 also locally trimethylates H3K36 at hotspots. Using ChIP-seq and immunoprecipitation data for H3K36me3 in murine spermatocytes, we show that H3K4me3 and H3K36me3 coincide only at hotspots in germ cells, and that this H3K4me3/H3K36me3-double-positive signature is almost entirely dependent on PRDM9.
2016-06-30 | GSE76416 | GEO
Project description:In many eukaryotes, meiotic recombination occurs preferentially at discrete sites, called recombination hotspots. In various lineages, recombination hotspots are located in regions with promoter-like features and are evolutionarily stable. Conversely, in some mammals, hotspots are driven by PRDM9 that targets recombination away from promoters. Paradoxically, PRDM9 induces the self-destruction of its targets and this triggers an ultra-fast evolution of mammalian hotspots. PRDM9 is ancestral to all animals, suggesting a critical importance for the meiotic program, but has been lost in many lineages with surprisingly little effect on meiosis success. However, it is unclear whether the function of PRDM9 described in mammals is shared by other species. To investigate this, we analyzed the recombination landscape of several salmonids, the genome of which harbors one full-length PRDM9 and several truncated paralogs. We identified recombination initiation sites in Oncorhynchus mykiss by mapping meiotic DNA double-strand breaks (DSBs). We found that DNA DSBs clustered at hotspots positioned away from promoters, enriched for the H3K4me3 and H3K36me3 marks and the location of which depended on the genotype of full-length Prdm9. We observed a high level of polymorphism in the zinc finger domain of full-length Prdm9, indicating diversification driven by positive selection. Moreover, population-scaled recombination maps in O. mykiss, Oncorhynchus kisutch and Salmo salar revealed a rapid turnover of recombination hotspots caused by PRDM9 target motif erosion. Our results imply that PRDM9 function is conserved across vertebrates and that the peculiar evolutionary runaway caused by PRDM9 has been active for several hundred million years.
2024-09-23 | GSE277449 | GEO
Project description:Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.
| S-EPMC7050486 | biostudies-literature
Project description:Vertebrate recombination concentrates in meiotic chromatin regions (hotspots) that are opened in some species by the DNA-sequence-specific-binding histone H3 trimethyltransferase PRDM9, while other species recombine in regions with already opened chromatin and other function. Inactivation of the mouse Prdm9 gene induces the shift of hotspots to functional regions, gross fertility reduction in males, and sterility in females. In contrast, the other vertebrate species lacking PRDM9 remain fertile. To resolve this discrepancy, we generated Prdm9 deletions in the Rattus norvegicus genome and generated the first rat genome-wide maps of recombination-initiating double-strand break hotspots. Rat strains carrying the same wild-type Prdm9 allele shared 88% hotspots but strains with different Prdm9 alleles only 3%. After Prdm9 deletion, rat hotspots relocated to functional regions, 40% to positions corresponding to Prdm9-independent mouse hotspots. Despite of hotspot relocation and of decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced apparently normal offspring. Rat PRDM9 thus makes recombination landscape unique, but it is unnecessary for recombination. This peculiarity is likely similar for human PRDM9 and may resolve the paradox between the apparently species-specific functions. PRDM9 is known to play a role in speciation, as it causes mouse hybrid sterility via meiotic asynapsis. Besides the expected mild meiotic arrest, we also detected apoptosis of postmeiotic spermatids, suggesting that PRDM9 has an additional role during spermatogenesis and perhaps also in speciation.
2021-03-25 | GSE163474 | GEO
Project description:Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. The DNA double strand breaks (DSBs) that initiate meiotic recombination are directed by sequence-specific DNA binding of the PRDM9 protein. Gradual elimination of PRDM9 binding sites by gene conversion is thought to result in the hotspot erosion while mutations affecting DNA binding specificity of PRDM9 will create the new sets of hotspots. To better understand evolutionary turnover of recombination hotspots we mapped DSB hotspots in six inbred mouse strains representing all four major subspecies of Mus musculus and in their F1 hybrids. We found that hotspot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hotspots that become active in the hybrids. As crossovers are disfavored at such hotspots, we propose that sequence divergence generated by hotspot turnover creates impediments for recombination in hybrids, potentially leading to reduction in fertility and eventually, speciation.
2016-02-03 | GSE75419 | GEO
Project description:Meiotic recombination is initiated by genome-wide SPO11-induced double-strand breaks (DSBs) that are processed by MRE11-mediated release of SPO11-bound oligonucleotides (SPO11-oligos). The DSB is then resected and loaded with DMC1/RAD51 filaments that invade homologous chromosome templates. In most mammals, DSB locations (“hotspots”) are determined by the DNA sequence specificity of the PRDM9 DNA binding zinc finger array. Here, we demonstrate the first direct detection of meiotic DSBs in vertebrates by performing END-seq on mouse spermatocytes using low sample input. We find that DMC1 limits both the minimum and maximum length of ssDNA produced at all hotspots, whereas 53BP1, BRCA1 and EXO1 play a surprisingly minimal role in meiotic resection. Through enzymatic modifications to the END-seq protocol that mimic the in vivo processing of SPO11, we identify a novel meiotic recombination intermediate (RI) with SPO11 still bound to the 3’ end via a small stretch of dsDNA (“SPO11-RI”) that is dependent on the presence of PRDM9. We propose that SPO11-RI is generated because chromatin-bound PRDM9 blocks MRE11 from releasing SPO11 via 3’-5’ resection. SPO11-RI is present at all hotspots and correlates with the localization and frequency of crossovers and noncrossovers. In Atm–/– spermatocytes, multiple DSBs at the same hotspot reduces SPO11-RI formation, while unresected DNA-bound SPO11 accumulates because of defective MRE11 initiation. Thus in addition to their global roles in governing SPO11 breakage, ATM and PRDM9 are critical local regulators of mammalian SPO11 processing.
2020-02-20 | GSE138915 | 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