DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans

Author summary Sexual reproduction relies on the production of sperm and eggs by the specialized cell division program called meiosis. Errors during meiosis often lead to miscarriages, infertility, and birth defects. Therefore, understanding the mechanisms regulating meiosis has major implications for human health. Chromatin modifiers have emerged as important regulators of a wide-range of cellular processes. However, despite their importance, their roles during meiosis remain poorly understood. Here, we show that C. elegans DOT-1.1, a conserved histone methyltransferase that catalyzes histone H3 lysine 79 (H3K79) methylation, regulates chromosome pairing, synapsis and recombination, thereby promoting normal meiotic progression and chromosome segregation. Moreover, we show that DOT-1.1 promotes a meiotic checkpoint function set in place to survey chromosome synapsis through a mechanism that appears to be distinct from the one described in budding yeast. Altogether, our study reveals a link between the regulation of H3K79me and the normal progression of meiosis. Epigenetic modifiers are emerging as important regulators of the genome. However, how they regulate specific processes during meiosis is not well understood. Methylation of H3K79 by the histone methyltransferase Dot1 has been shown to be involved in the maintenance of genomic stability in various organisms. In S. cerevisiae, Dot1 modulates the meiotic checkpoint response triggered by synapsis and/or recombination defects by promoting Hop1-dependent Mek1 activation and Hop1 distribution along unsynapsed meiotic chromosomes, at least in part, by regulating Pch2 localization. However, how this protein regulates meiosis in metazoans is unknown. Here, we describe the effects of H3K79me depletion via analysis of dot-1.1 or zfp-1 mutants during meiosis in Caenorhabditis elegans. We observed decreased fertility and increased embryonic lethality in dot-1.1 mutants suggesting meiotic dysfunction. We show that DOT-1.1 plays a role in the regulation of pairing, synapsis and recombination in the worm. Furthermore, we demonstrate that DOT-1.1 is an important regulator of mechanisms surveilling chromosome synapsis during meiosis. In sum, our results reveal that regulation of H3K79me plays an important role in coordinating events during meiosis in C. elegans.