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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.

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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.

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2016-06-30 | E-GEOD-76416 | biostudies-arrayexpress

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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.

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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.

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