The histone modification reader ZCWPW1 promotes double-strand break repair by regulating cross-talk of histone modifications and chromatin accessibility at meiotic hotspots

BACKGROUND: The PRDM9-dependent histone methylation H3K4me3 and H3K36me3 function in assuring accurate homologous recombination at recombination hotspots in mammals. Beyond histone methylation, H3 lysine 9 acetylation (H3K9ac) is also greatly enriched at recombination hotspots. Previous work has indicated the potential cross-talk between H3K4me3 and H3K9ac at recombination hotspots, but it is still unknown what molecular mechanisms mediate the cross-talk between the two histone modifications at hotspots or how the cross-talk regulates homologous recombination in meiosis. RESULTS: Here, we find that the histone methylation reader ZCWPW1 is essential for maintaining H3K9ac by antagonizing HDAC proteins’ deacetylation activity and further promotes chromatin openness at recombination hotspots thus preparing the way for homologous recombination during meiotic double-strand break repair. Interestingly, ectopic expression of the germ-cell-specific protein ZCWPW1 in human somatic cells enhances double-strand break repair via homologous recombination. CONCLUSIONS: Taken together, our findings provide new insights into how histone modifications and their associated regulatory proteins collectively regulate meiotic homologous recombination. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02758-z.