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Genetics of mammalian meiosis
Published in C. Yan Cheng, Spermatogenesis, 2018
Meiotic recombination occurs more frequently at certain genomic locations (so-called hotspots) than others.93 The major advance in the study of recombination hotspot is the identification of PRDM9. PRDM9 is a main determinant of meiotic recombination hotspots in mammals.94–96 PRDM9 binds to the 13-mer hotspot consensus DNA motif through its array of DNA-binding zinc fingers. PRDM9 catalyzes both trimethylation of lysine 4 of histone H3 (H3K4me3)97 and trimethylation of lysine 36 of histone H3 (H3K36me3).98 Meiotic recombination hotspots are marked by both H3K4me3 and H3K36me3 modifications.99 H4K44 acetylation (H4K44ac) marks meiotic recombination hotspots in budding yeast but its relationship with mammalian hotspots is unknown.100 PRDM9 directs recombination away from functional genomic elements such as gene promoters.101 The Prdm9 gene is rapidly evolving, especially in the zinc-finger coding region.102 This rapid evolution is driven by the inherent “self-destruct” property of recombination hotspots.95 A recombination hotspot is favored for DSB formation and thus is more likely to be replaced with a coldspot allele through homologous recombination. The 13-mer hotspot consensus motif varies in sequences among species. As a new hotspot consensus emerges, the zinc-finger region of PRMD9 evolves to bind to the new hotspots and vice versa. For example, humanizing the zinc-finger domain of PRDM9 in mice changes the positions of DSB hotspots in mouse.103Prmd9 is the only known mammalian speciation gene and is responsible for the hybrid sterility between mouse subspecies.104 How are H3K4me3-marked hotspots recognized for DSB formation? Recent studies provide insights into the connection of the hotspot to DSB. PRMD9 binding leads to nucleosome depletion at the hotspot, a possible permissive environment for DSB formation.105 PRDM9 interacts with CXXC1, which in turn interacts with IHO1.106 IHO1 is a part of the protein complex that activates SPO11. In addition to CXXC1, PRDM9 interacts with EWSR1, EHMT2, and CDYL.107 In testis, PRDM9 is complexed with REC8, SYCP1, and SYCP3.107 Therefore, the epigenetic and chromatin states specify the location of DSBs and PRDM9 is recruited through association with cohesin and SC.
Recent advances in histone modification and histone modifying enzyme assays
Published in Expert Review of Molecular Diagnostics, 2019
Fei Ma, Su Jiang, Chun-yang Zhang
As an alternative to the antibody-based assays, supra-molecular tandem assay employs the small molecule synthetic receptors as the host molecules instead of the antibody to detect the interest target molecules [52]. The integration of supra-molecular tandem assay with the fluorescence displacement technique has distinct advantages of high sensitivity, low cost, rapidity, and simplicity, and has been successfully applied for the detection of proteases, decarboxylases, cholinesterases, and histone modifying enzymes [53–55]. Zhong and colleagues developed an arrayed supramolecular tandem assay for the detection of histone methylation enzyme activity [39]. The cavitand is a container-shaped molecule which can engage guest molecules with a complementary shape and size [56]. In this assay, the array is constructed by the incorporation of three cavitands with guest fluorophore whose fluorescence is efficiently quenched by the cavitands. The addition of target peptide (i.e. the modification product of histone methyltransferase PRDM9) will displace the fluorophore, inducing the recovery of fluorescence signal. This assay can specifically detect target enzymes in a complex environment with the presence of interfering peptides, facilitating the study of cross-reactivity over multiple methylation sites.