Yukiko Imai, Mathilde Biot, Julie Clément, Mariko Teragaki, Serge Urbach, Thomas Robert, Frédéric Baudat, Corinne Grey, Bernard de Massy
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...
October 13, 2020: ELife
Samuel J Widmayer, Mary Ann Handel, David L Aylor
Hybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse ( Mus musculus ) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome...
August 17, 2020: Genetics
Daniel Wells, Emmanuelle Bitoun, Daniela Moralli, Gang Zhang, Anjali Hinch, Julia Jankowska, Peter Donnelly, Catherine Green, Simon R Myers
During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identified Zcwpw1 , containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression with Prdm9 . Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone...
August 3, 2020: ELife
Amisa Mukaj, Jaroslav Piálek, Vladana Fotopulosova, Andrew Parker Morgan, Linda Odenthal-Hesse, Emil D Parvanov, Jiri Forejt
The classical definition posits hybrid sterility as a phenomenon when two parental taxa each of which is fertile produce a hybrid that is sterile. The first hybrid sterility gene in vertebrates, Prdm9, coding for a histone methyltransferase, was identified in crosses between two laboratory mouse strains derived from Mus m. musculus and Mus m. domesticus subspecies. The unique function of PRDM9 protein in the initiation of meiotic recombination led to the discovery of the basic molecular mechanism of hybrid sterility in laboratory crosses...
July 8, 2020: Molecular Biology and Evolution
Kento Morimoto, Koki Numata, Yoko Daitoku, Yuko Hamada, Keiko Kobayashi, Kanako Kato, Hayate Suzuki, Shinya Ayabe, Atsushi Yoshiki, Satoru Takahashi, Kazuya Murata, Seiya Mizuno, Fumihiro Sugiyama
F1 hybrid progenies between related subspecies often show hybrid sterility (HS) or inviability. HS is caused by failure of meiotic chromosome synapsis and sex body formation in house mouse. Previous studies identified two HS critical genomic regions named Hstx2 on Chr X and Hst1 on Chr 17 by murine forward genetic approaches. HS gene on Hst1 was reported to be Prdm9. Intersubspecific polymorphisms of Prdm9 induce HS in hybrids, and Prdm9 null mutation leads to sterility in the inbred strain. However, HS gene on Hstx2 remains unknown...
June 3, 2020: Scientific Reports
Melak Weldenegodguad, Kisun Pokharel, Yao Ming, Mervi Honkatukia, Jaana Peippo, Tiina Reilas, Knut H Røed, Juha Kantanen
Reindeer are semi-domesticated ruminants that have adapted to the challenging northern Eurasian environment characterized by long winters and marked annual fluctuations in daylight. We explored the genetic makeup behind their unique characteristics by de novo sequencing the genome of a male reindeer and conducted gene family analyses with nine other mammalian species. We performed a population genomics study of 23 additional reindeer representing both domestic and wild populations and several ecotypes from various geographic locations...
June 2, 2020: Scientific Reports
Tao Huang, Shenli Yuan, Lei Gao, Mengjing Li, Xiaochen Yu, Jianhong Zhang, Yingying Yin, Chao Liu, Chuanxin Zhang, Gang Lu, Wei Li, Jiang Liu, Zi-Jiang Chen, Hongbin Liu
The histone modification writer Prdm9 has been shown to deposit H3K4me3 and H3K36me3 at future double-strand break (DSB) sites during the very early stages of meiosis, but the reader of these marks remains unclear. Here, we demonstrate that Zcwpw1 is an H3K4me3 reader that is required for DSB repair and synapsis in mouse testes. We generated H3K4me3 reader-dead Zcwpw1 mutant mice and found that their spermatocytes were arrested at the pachytene-like stage, which phenocopies the Zcwpw1 knock-out mice. Based on various ChIP-seq and immunofluorescence analyses using several mutants, we found that Zcwpw1's occupancy on chromatin is strongly promoted by the histone-modification activity of PRDM9...
May 6, 2020: ELife
Shintaro Yamada, Anjali Gupta Hinch, Hisashi Kamido, Yongwei Zhang, Winfried Edelmann, Scott Keeney
Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5' → 3' exonuclease, but the DSB-responsive kinase ATM proved a key regulator of both initiation and extension of resection...
April 30, 2020: Genes & Development
Li Na Zhao, Philipp Kaldis
The S-adenosyl-L-methionine (SAM)-dependent methyltransferases attach a methyl group to the deprotonated methyl lysine (Kme0) using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation of the methyl lysine takes place which results in a lone pair of electrons at the Nϵ atom of the methyl lysine for the following methyl transfer. PRDM9, one of the few methyltransferases with well-defined enzyme activity in vitro and in vivo, is a good representative of the PR/SET domain methyltransferase family to study the deprotonation and subsequently the methyl transfer...
April 30, 2020: FEBS Letters
Mohamed Mahgoub, Jacob Paiano, Melania Bruno, Wei Wu, Sarath Pathuri, Xing Zhang, Sherry Ralls, Xiaodong Cheng, André Nussenzweig, Todd S Macfarlan
Meiotic crossovers result from homology-directed repair of DNA 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). PRDM9 subsequently catalyzes tri-methylation 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 , as an essential meiotic recombination factor required for efficient repair of PRDM9-dependent DSBs and for pairing of homologous chromosomes in male mice...
April 30, 2020: ELife
Fitore Kusari, Ondrej Mihola, John C Schimenti, Zdenek Trachtulec
Reduced fertility of male mouse hybrids relative to their parents, or hybrid sterility, is governed by the hybrid sterility 1 (Hst1) locus. Rescue experiments with transgenes carrying sequences within or near Hst1 manifested that Hst1 contains the gene encoding meiosis-specific histone methyltransferase PRDM9. The Prdm9 gene is responsible for partial meiotic arrest, testicular atrophy, and low sperm count in (C57BL/6J x PWD)F1 mouse hybrids. Here we report that these male hybrids suffer an additional reproductive disadvantage, decreased sperm quality, which is (i) further exacerbated by the introduction of long transgenes carrying sequences from Hst1 with incomplete Prdm9 into their genome and (ii) controlled by the Prdm9 dosage...
July 2020: Reproduction
Kris G Alavattam, Hironori Abe, Satoshi H Namekawa
To induce cell type-specific forms of gene regulation, pioneer factors open tightly packed, inaccessible chromatin sites, enabling the molecular machinery to act on functionally significant information encoded in DNA. While previous studies of pioneer factors have revealed their functions in transcriptional regulation, pioneer factors that open chromatin for other physiological events remain undetermined. In this issue of Genes & Development , Spruce and colleagues (pp. 398-412) report the functional significance of a "pioneer complex" in mouse meiotic recombination...
March 1, 2020: Genes & Development
Jacob Paiano, Wei Wu, Shintaro Yamada, Nicholas Sciascia, Elsa Callen, Ana Paola Cotrim, Rajashree A Deshpande, Yaakov Maman, Amanda Day, Tanya T Paull, André Nussenzweig
Meiotic recombination is initiated by SPO11-induced double-strand breaks (DSBs). In most mammals, the methyltransferase PRDM9 guides SPO11 targeting, and the ATM kinase controls meiotic DSB numbers. Following MRE11 nuclease removal of SPO11, the DSB is resected and loaded with DMC1 filaments for homolog invasion. Here, we demonstrate the direct detection of meiotic DSBs and resection using END-seq on mouse spermatocytes with low sample input. We find that DMC1 limits both minimum and maximum resection lengths, whereas 53BP1, BRCA1 and EXO1 play surprisingly minimal roles...
February 12, 2020: Nature Communications
Yao Chen, Ruitu Lyu, Bowen Rong, Yuxuan Zheng, Zhen Lin, Ruofei Dai, Xi Zhang, Nannan Xie, Siqing Wang, Fuchou Tang, Fei Lan, Ming-Han Tong
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...
February 11, 2020: Cell Research
Alexey V Boyko, Alexander S Girich, Ekaterina S Tkacheva, Igor Yu Dolmatov
The holothurian Eupentacta fraudatrix is a unique organism for studying regeneration mechanisms. Moreover, E. fraudatrix can quickly restore parts of its body and entire organ systems, yet at the moment, there is no data on the participation of stem cells in the process. To the contrary, it has been repeatedly confirmed that this process is only due to the transformation of terminally differentiated cells. In this study, we examine changes in gene expression during gut regeneration of the holothurian E. fraudatrix...
January 30, 2020: Scientific Reports
Catrina Spruce, Sibongakonke Dlamini, Guruprasad Ananda, Naomi Bronkema, Hui Tian, Kenneth Paigen, Gregory W Carter, Christopher L Baker
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...
January 30, 2020: Genes & Development
Yong-Chang Li, Guo-Wen Wang, Shang-Rong Xu, Xiao-Na Zhang, Qi-En Yang
Interspecies hybridization exists widely in nature and plays an important role in animal evolution and adaptation. It is commonly recognized that male offspring of interspecies hybrid are often sterile, which presents a crucial way of reproductive isolation. Currently, the mechanisms underlying interspecies hybrid male sterility are not well understood. Cattle-yak, progeny of yak (Bos grunniens) and cattle (Bos taurus) cross, is a unique animal model for investigating hybrid male sterility. Because histone modifications are vital for spermatogenesis, herein, we examined expressions of histone methyltransferases (HMTs) and distributions of histone methylations in the yak and cattle-yak testis...
January 7, 2020: Theriogenology
Ondrej Mihola, Tatyana Kobets, Klara Krivankova, Eliska Linhartova, Srdjan Gasic, John C Schimenti, Zdenek Trachtulec
Long transgenes are often used in mammalian genetics, e.g., to rescue mutations in large genes. In the course of experiments addressing the genetic basis of hybrid sterility caused by meiotic defects in mice bearing different alleles of Prdm9, we discovered that introduction of copy-number variation (CNV) via two independent insertions of long transgenes containing incomplete Prdm9 decreased testicular weight and epididymal sperm count. Transgenic animals displayed increased occurrence of seminiferous tubules with apoptotic cells at 18 days postpartum (dpp) corresponding to late meiotic prophase I, but not at 21 dpp...
January 15, 2020: Chromosoma
Drew R Schield, Giulia I M Pasquesi, Blair W Perry, Richard H Adams, Zachary L Nikolakis, Aundrea K Westfall, Richard W Orton, Jesse M Meik, Stephen P Mackessy, Todd A Castoe
Meiotic recombination in vertebrates is concentrated in hotspots throughout the genome. The location and stability of hotspots have been linked to the presence or absence of PRDM9, leading to two primary models for hotspot evolution derived from mammals and birds. Species with PRDM9-directed recombination have rapid turnover of hotspots concentrated in intergenic regions (i.e., mammals), whereas hotspots in species lacking PRDM9 are concentrated in functional regions and have greater stability over time (i...
May 1, 2020: Molecular Biology and Evolution
Masoumeh Majidi Zolbin, Gulcin Sahin Ersoy, Fereshte Aliakbari, Fardin Amidi, Faezeh Daghigh, Mehdi Abbasi, Joshua Johnson
Lately, stem cell approaches have provided new information on reproductive organ function and additionally recommended novel treatment possibilities. The type(s) and differentiation potential of stem cells present in the mammalian ovary are largely unknown; while oogonial stem cells have been reported, we explored the possibility that multipotent stem cells may reside in the ovary and have wide differentiation potential. In this experimental study, homogenates of whole mouse ovaries were sorted using the stem cell surface markers stem cell antigen-1 and stage specific embryonic antigen-1/CD15...
January 2020: In Vitro Cellular & Developmental Biology. Animal
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