SPR-1/CoREST facilitates the maternal epigenetic reprogramming of the histone demethylase SPR-5/LSD1

Abstract Maternal reprogramming of histone methylation is critical for reestablishing totipotency in the zygote, but how histone-modifying enzymes are regulated during maternal reprogramming is not well characterized. To address this gap, we asked whether maternal reprogramming by the H3K4me1/2 demethylase SPR-5/LSD1/KDM1A, is regulated by the chromatin co-repressor protein, SPR-1/CoREST, in Caenorhabditis elegans and mice. In C. elegans, SPR-5 functions as part of a reprogramming switch together with the H3K9 methyltransferase MET-2. By examining germline development, fertility, and gene expression in double mutants between spr-1 and met-2, as well as fertility in double mutants between spr-1 and spr-5, we find that loss of SPR-1 results in a partial loss of SPR-5 maternal reprogramming function. In mice, we generated a separation of function Lsd1 M448V point mutation that compromises CoREST binding, but only slightly affects LSD1 demethylase activity. When maternal LSD1 in the oocyte is derived exclusively from this allele, the progeny phenocopy the increased perinatal lethality that we previously observed when LSD1 was reduced maternally. Together, these data are consistent with CoREST having a conserved function in facilitating maternal LSD1 epigenetic reprogramming. Carpenter, Scott et al. use C. elegans and mouse to investigate whether chromatin co-repressor protein SPR-1/CoREST functions in the maternal epigenetic reprogramming carried out by histone demethylase SPR-5/LSD1. They provide mechanistic insight into how maternal LSD1 reprogramming is regulated, demonstrating that CoREST has a conserved function helping LSD1 more efficiently reprogram chromatin maternally. In addition, they provide further evidence of a novel paradigm where defects in maternal LSD1 reprogramming at fertilization in mice can lead to phenotypes that manifest postnatally.