Epigenetic regulation in mammalian preimplantation embryo development

Abstract

Preimplantation embryo development involves four stages: fertilization, cell cleavage, morula and blastocyst formation. During these stages, maternal and zygotic epigenetic factors play crucial roles. The gene expression profile is changed dramatically, chromatin is modified and core histone elements undergo significant changes. Each preimplantation embryo stage has its own characteristic epigenetic profile, consistent with the acquisition of the capacity to support development. Moreover, histone modifications such as methylation and acetylation as well as other epigenetic events can act as regulatory switches of gene transcription. Because the epigenetic profile is largely related to differentiation, epigenetic dysfunction can give rise to developmental abnormalities. Thus, epigenetic profiling of the embryo is of pivotal importance clinically. Given the importance of these aspects, this review will mainly focus on the epigenetic profile during preimplantation embryo development, as well as interactions between epigenetic and genetic regulation in these early developmental stages.

Figure 1

General view of the main epigenetic reprogramming pathways in preimplantation development. (A) DNA methylation reprogramming in the mouse embryo. Active demethylation happens in paternal PN(pronucleus) followed by passive demethylation of the entire genome during cleavage stage. Then comes de novo methylation when the embryo commences cell differentiating. (B) Histone modification reprogramming, from fertilization to syngamy. In the paternal PN, sperm nuclear protamines are gradually replaced by highly acetylated histones, which are immediately substituted by monomethylated ones. Dimethylated and trimethylated histones appear later. In the maternal PN, all the modifications listed can be detected in this period. H3K9me3 is found in centromeric major satellites, whereas H3K9me2 is found in minor satellites.

Figure 2

X chromosome inactivation and regulatory mechanisms. (A) The Xic region of the X chromosome and several regulatory elements in this region. Xist loci encodes a ncRNA which mediates the initiation of XCI. Xist is negatively regulated by another ncRNA, Tisx, which is complementary to Xist. Xite is a special upstream enhancer of Tisx. (B) By pairing at the Xic region, X chromosomes communicate and counting, selecting are then undergone to make sure that only one X chromosome remains active. Xa, active X chromosome; Xi, inactive X chromosome. (C) Mechanisms from initiation of XCI to the short- and long-term maintenance of silencing status. After selection, Xist coats the Xi chromosome to initiate XCI. A ncRNA (RepA) then usher polycomb repressive complex 2 (PRC2) to the Xi chromosome, recruiting histone modification changes such as H2A-K119 ubiquitination (U) and H3K27 methylation (M). Histone modifications bring about short-term silencing followed by histone variant incorporation (macroH2A) and de novo DNA methylation, mediating long-term silencing.

Figure 3

Some examples of interactions between genetics and epigenetics. (A) The Ped gene protein product Qa-2 affects the level of an epigenetic element (miR-125a) to participate in the interaction. (B) The LINE-1(L1) retrotransposon expression is precisely regulated by epigenetic mechanisms (negatively by RNAi and positively by demethylation), while its expression and activation can effect gene expression both genetically and epigenetically. When genetically, large and short insertion cause elongation disruption or attenuation. When epigenetically, expression of L1 disrupts or attenuates gene expression without insertion. (C) Ronin (R) binds DNA directly; once bound it recruits HCF-1 (Hc) and other proteins that are related with transcriptional repression or histone modifications, among which are THAP7 (T), sin3A (S) and HDAC3 (Hd), to form a large protein complex and regulate histone modifications (methylation and deacetylation) so as to affect gene expression.

Figure 4

Epigenetic and genetic interactions during early preimplantation development. After fertilization, some maternally-derived epigenetic participants (e.g. DNMTs, Ago2) remain to be involved in gene expression transition(ZGA) and alter the gene expression status, leading to the expression of more epigenetic participants and other genes. These newly expressed ones are then added to further regulate the gene expression and developmental events.