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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE144144 | GEO | 2020/10/23

REPOSITORIES: GEO

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Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudo-modularity

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. We previously reported two hypomorphic catalytic mutations, Prdm9-EP and Prdm9-EK, with different phenotypic effects. Prdm9-EP, but not Prdm9-EK, is compatible with female sub-fertility, while both mutations phenocopy the Prdm9-null condition in males. Here we directly compare and contrast the enzymatic effects of the two mutations in vitro and in vivo. We previously performed two biological H3K4me3 ChIP-seq replicates in spermatocytes isolated from Prdm9-EP homozygous males (GSE144144; SRX8588740 and SRX8588741), and re-processed previously reported H3K4me3 ChIP-seq data from spermatocytes isolated from wild-type B6 males (GSE52628; SRX381465 and SRX381466). We used those raw and processed files for this study (GSE144144). We also previously performed one biological H3K4me3 replicate in spermatocytes isolated from Prdm9-EP homozygous males (GSE112110; SRX4136625). We report an additional replicate here, and merged the two replicates for analysis; raw and processed files are reported here. We also performed ChIP-seq for H3K36me3 in both Prdm9-EP and Prdm9-EK homozygous spermatocytes. Raw and processed files are available here. For comparison, we re-mapped and re-analyzed H3K36me3 ChIP-seq data we previously reported from wild-type B6 spermatocytes (GSE76416; SRX1508234); processed files are available here.

2021-10-11 | GSE181479 | GEO

ATM and PRDM9 Regulate SPO11-bound Recombination Intermediates During Meiosis

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

A high-resolution binding profile of meiotic cohesin in murine spermatocytes reveals accumulation at rDNA loci

Project description:In mammalian spermatocytes and oocytes, cohesin complexes serve several distinct functions including establishing the meiotic chromosome architecture into axes and loops, providing sister chromatid cohesion, protecting telomeres, and supporting meiotic recombination. High-resolution analysis of cohesin binding to meiotic chromosomes, however, remained to be performed, mainly because of the complexity of germ cell development and meiotic chromatin, and of the difficulty obtaining proper meiocyte populations. Here, we established a ChIP-seq approach to identify and characterize the genome-wide binding profile of cohesin specifically in murine spermatocytes. Chromatin binding of cohesin proteins SMC3, present in all cohesin complexes, and SMC1β representing the major meiotic complexes, were analyzed. Both cohesins were much reduced in coding exons as well as in 5’ and 3’ UTRs. SMC1β cohesin binding sequences coincide in a large fraction with CACA repeats and thus with transcription factor ZSCAN4C binding sites, but also with other TF sites. We observed neither overlap with recombinase DMC1 sites nor with recombination hotspot marker PRDM9 sites. Most interestingly, meiotic cohesin is strongly enriched at 5S ribosomal RNA genes. We hypothesize a role of cohesin in the regulation of meiotic rDNA stability and/or transcription.

2016-10-21 | GSE88972 | GEO

The meiotic recombination activator PRDM9 trimethylates both H3K4 and H3K36 at recombination hotspots in vivo

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

FIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in meiotic DNA replication and recombination

Project description:The formation of RAD51/DMC1 filaments on single-stranded (ss)DNAs, which is essential for homology search and strand exchange in DNA double-strand break (DSB) repair and for the protection of stalled DNA replication forks, is tightly regulated in time and space. FIGNL1 AAA+++ ATPase plays positive and negative roles in the RAD51-mediated recombination in human cells. However, the role of FIGNL1 in gametogenesis remains unsolved. Here, we characterized a germ-line-specific conditional knockout (cKO) mouse of FIGNL1. The Fignl1 cKO male mice showed defective chromosome synapsis and impaired meiotic DSB repair with the accumulation of RAD51/DMC1 on chromosomes in mid-meiotic prophase I, supporting a role of FIGNL1 in a post-assembly stage of RAD51/DMC1 filaments. Fignl1 cKO spermatocytes accumulate RAD51 and DMC1 ensembles on chromosomes not only in early meiotic prophase I but also in meiotic S-phase. These RAD51/DMC1 assemblies are independent of meiotic DSB formation. Finally, we showed that purified FIGNL1 dismantles RAD51 filament on double-stranded (ds)DNA as well as ssDNA. These results suggest a critical role of FIGNL1 to limit the uncontrolled assembly of RAD51 and DMC1 on native dsDNAs during the meiotic S-phase and meiotic prophase I.

2023-03-31 | GSE227944 | GEO

Genome-wide maps of ZCWPW1 in HEK293T cells with or without PRDM9, plus DMC1 ChIP-seq in ZCWPW1 KO mouse

Project description:During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified. We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. In this study we used ChIP-sequencing in human HEK293T cells (co)-transfected with HA tagged ZCWPW1 (and human or chimp PRDM9). This enabled us to determine that PRDM9 causes the recruitment of ZCWPW1 to its binding sites, and to determine the general binding properties of ZCWPW1 including a preference for CpG sites. We also performed SSDS ChIP-sequencing of mice testis that are homozygous KO for ZCWPW1, revealing that double strand breaks occour at completely normal positions in the ZCWPW1 KO, but with persistant DMC1 at many hotspots, particularly those more strongly bound by PRDM9.

2020-08-01 | GSE141516 | GEO

Genome wide maps of Dmc1 in testis of Hop2 null mice.

Project description:We report the application of ChIP-seq targeted at the meiosis-specific protein DMC1 to reveal the genome-wide distribution of initiation of meiotic recombination. The mouse model here employed is Hop2-/- because it is unable to repair the DNA double-stranded breaks and therefore the DMC1 signal is more persistent. We also provide the resulting dataset of ChIP-seq targeted at RAD51 which is not meiosis specific but is also targeted at initiation of recombination loci in meiotic tissue. In addition, we report DMC1 ChIP-seq on wild type mouse pup testis. Finally, we present ChIP-seq targeted at H3K4me3 in testis and liver tissues.

2011-04-04 | GSE24438 | GEO

Mus musculus

Project description:Humanized PRDM9 Mouse Testis H3K4me3 and DMC1 ChIP-seq

| PRJNA298164 | ENA

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

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

| PRJNA514744 | ENA

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

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