As well as genetic information, the egg and sperm also contribute epigenetic annotations that may influence gene activity after fertilisation. These annotations may be direct modifications of the DNA bases or of the proteins around which the DNA is wrapped into chromatin. Our goal is to understand whether, through epigenetics, factors such as a mother’s age or diet have consequences on the health of a child. We examine how epigenetic states are set up in oocytes – or egg cells – and influence gene expression in the embryo. For example, repressive chromatin marks in oocytes lead to long-term silencing of genes inherited from the mother, particularly in cells that will form the placenta. We are also interested in how variations in DNA methylation come about in oocytes and whether we can use this variation as a marker for oocyte quality and embryo potential. To investigate these questions, we develop methods to profile epigenetic information in very small numbers of cells or even in single cells.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors.
Wnt4 signaling promotes somatic cell development in the female embryo, but its role in germline differentiation during meiosis remains poorly characterized. To explore Wnt4 functions in female embryonic gonads, we isolated germ cells from Wnt4 knock-out mice to investigate histone modifications and DNA methylation distribution patterns. The lack of the Wnt4 signaling pathway deregulates germ cell cycle markers, such as cyclins, alters the cell cycle by impairing meiosis progression, maintains the germ cells in the G1-GO and S phases, and supporting DNMT3A and DNMT1 enzyme expression at meiosis entry. Conversely, in the nucleus of the Wnt4 knock-out female germ cells, an increase of H3K27me3 pattern persists at the entry of meiosis, leading to altered methylation at the Sycp3 promoters combined with an acetylation of Stra8 promoter at E14.5. This changed pattern might be explained by the overexpression of Creb-binding protein (CBP) in the mutant female germ cells, leading to deregulation of histone marks on meiosis genes. Our findings reveal that the Wnt4 signal is necessary for inducing meiosis by inhibiting germ cell proliferation via the regulation of histone modification. Wnt4 signaling plays a crucial role in regulating the delicate balance between DNA methylation and acetylation in female germ cells. This fascinating interaction highlights the complexities of cellular processes that contribute to reproductive health and development.
Nlrp5 encodes a core component of the subcortical maternal complex (SCMC) a cytoplasmic protein structure unique to the mammalian oocyte and cleavage-stage embryo. NLRP5 mutations have been identified in patients presenting with early embryo arrest, recurrent molar pregnancies and imprinting disorders. Correct patterning of DNA methylation over imprinted domains during oogenesis is necessary for faithful imprinting of genes. It was previously shown that oocytes with mutation in the human SCMC gene KHDC3L had globally impaired methylation, indicating that integrity of the SCMC is essential for correct establishment of DNA methylation at imprinted regions. Here, we present a multi-omic analysis of an Nlrp5-null mouse model, which in germinal vesicle (GV) stage oocytes displays a misregulation of a broad range of maternal proteins, including proteins involved in several key developmental processes. This misregulation likely underlies impaired oocyte developmental competence. Amongst impacted proteins are several epigenetic modifiers, including a substantial reduction in DNMT3L; we show that de novo DNA methylation is attenuated in Nlrp5-null oocytes, including at some imprinting control regions. This provides evidence for a mechanism of epigenetic impairment in oocytes which could contribute to downstream misregulation of imprinted genes.