Grant: Project Grant

All cells in a complex organism harbor the same genetic content yet can express different sets of genes to give cell type specific functions. This diversity is created by the deposition of epigenetic modifications on the genome, which create compact (transcriptionally repressed) or open (transcriptionally active) chromatin states. The transition from oocyte to early embryo is characterized by an essential global remodelling of these epigenetic modifications to create all the different cell types of an embryo. Epigenetic anomalies are found in several human disorders, including infertility, overgrowth syndromes and impaired development. Recently, mutations in the Heterochromatin Protein 1 (HP1) group of proteins were identified in cases of recurrent miscarriages and neurodevelopmental disorders. HP1s are involved in creating a compact environment that represses gene expression. We hypothesize that their malfunction in the oocyte and in the early stages following fertilization will create epigenetic errors in the growing embryo. In turn, these errors will negatively affect the development of specific tissues and, in more severe cases, lead to fetal death. In this study, we will use the latest genome-wide technologies to investigate the necessity of HP1s to establish appropriate gene expression programs during the transition from oocyte to early embryo. In addition, we will employ state-of-the-art imaging and micromanipulation techniques in mouse oocytes and embryos to understand how epigenetic errors introduced by mutant HP1s can impair specific cellular functions and lead to pathologies. Understanding when and how mutant HP1s can create epigenetic mistakes is essential to identify adequate treatment or prevention approaches in fertility clinics.