NLRPs, the subcortical maternal complex and genomic imprinting

Abstract

Before activation of the embryonic genome, the oocyte provides many of the RNAs and proteins required for the epigenetic reprogramming and the transition to a totipotent state. Targeted disruption of a subset of oocyte-derived transcripts in mice results in early embryonic lethality and cleavage-stage embryonic arrest as highlighted by the members of the subcortical maternal complex (SCMC). Maternal-effect recessive mutations of NLRP7, KHDC3L and NLRP5 in humans are associated with variable reproductive outcomes, biparental hydatidiform moles (BiHM) and widespread multi-locus imprinting disturbances. The precise mechanism of action of these genes is unknown, but the maternal-effect phenomenon suggests a function during early pre-implantation development, while biochemical and genetic studies implement them as SCMC members or interacting partners. In this review article, we discuss the role of the NLRP family members and the SCMC proteins in the establishment of genomic imprints and post-zygotic methylation maintenance, the recent advances made in the understanding of the biology involved in BiHM formation and the wider roles of the SCMC in mammalian reproduction.Reproduction (2017) 154 R161-R170

Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers

“…On the other hand, the lack of variants in NLRP7 in the cohort of families with the loss of the paternal imprint at the ICR1 is compatible with the observation that NRLP7 variants are exclusively associated with the loss of maternal imprints, corresponding to its suggested role in oocyte-specific methylation establishment (for review: ref. [14]).…”

“…in the aforementioned gene ZFP57 [8]) or in their mothers (for review: ref. [14]). In particular, the primordial germ cells of a developing embryo as well as the (early) embryo itself undergo an epigenetic reprogramming.…”

“…In fact, there is a growing number of reports corroborating this observation (for review: ref. [14]). Several of these genes are members of the NLRP gene family, among them NLRP2, NLRP5, and NLRP7.…”

Recent Insights into the Mechanisms ofDe Novoand Maintenance of DNA Methylation in Mammals

“…It is reported that mutations in genes encoding zinc finger protein 57 (ZFP57) and components of subcortical maternal complex (SCMC), including NLRP2, NLRP5, NLRP7, PADI6, OOEP, and TLE6, cause the multi-locus imprint disorder, which exhibits DNA hypomethylation at multiple imprinting control regions (ICRs) [58][59][60][61]. Since the hypomethylation is observed in both paternally and maternally methylated ICRs, these factors are thought to be involved in maintenance of DNA methylation against genome-wide DNA demethylation in preimplantation embryos (Figure 1).…”

“…As ZFP57 is a nuclear protein, which recognizes the methylated TGCCGC hexanucleotide found in almost all ICRs and which acts together with ZNF445, KRAB-associated protein-1 (KAP1), DNMTs, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), and heterochromatin protein 1 (HP1) [62,63], ZFP57 is considered to maintain DNA methylation by directly binding to ICRs with such proteins. However, the mechanism by which SCMC components, which are localized adjacent to the oocyte membrane, can maintain DNA methylation at ICRs remains elusive [59]. Among the multi-locus imprint disorder cases, just one case, who has a heterozygous mutation (V159 M in isoform 1, V172 M in isoform 2) in the TTD of UHRF1, has been reported [60].…”