CoREST has a conserved role in facilitating SPR-5/LSD1 maternal reprogramming of histone methylation

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 co-repressor protein, SPR-1/CoREST in C. 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, we find that spr-1 mutants are partially compromised for spr-5; met-2 reprogramming. 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.

A developmental role for the chromatin-regulating CoREST complex in the cnidarian Nematostella vectensis

“…The CoREST complex and CoREST proteins have been shown to play roles in the differentiation and homeostasis of various tissues, including the nervous system [32][33][34][35][36][37], epidermis [38], immune system [39], and the hematopoietic system [40] in mammals. In Drosophila, dLsd1 and CoRest play roles in spermatogenesis and follicle cell differentiation in the ovary [29,41,42] while in C. elegans homologs of both are involved in reprogramming of the zygotic genome after fertilization, something which is conserved in mice [43][44][45].…”