Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of PRDM9-Induced Meiotic Double Strand Breaks

Meiotic crossovers result from homology-directed repair of 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), which subsequently catalyzes trimethylation 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 and co-evolved with Prdm9 in vertebrates, as an essential meiotic recombination factor required for efficient synapsis and repair of PRDM9-dependent DSBs. In sum, our results indicate that the evolution of dual histone methylation reader/writer system involving Prdm9 and Zcwpw1 facilitated a shift in genetic recombination away from a static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9 (1) CUT&RUN experiment for mapping chromatin binding of ZCWPW1 and H3K4me3 were performed on testis from adult C57BL/6N (B6/B6) mouse and F1 B6/CAST hybrid mouse from mating male CAST (CAST/EiJ ) and female B6 (C57BL/6J). (2) END-seq experiments were performed on testes from juvenile/adult Zcwpw1WT/WT and Zcwpw1WT/KO to map meiotic hotspots for DNA double strand breaks (DSBs)