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For a new individual to develop from a fertilized egg, it is required that certain regions of the genome (the DNA molecules), including the genes in these regions, become activated. After fertilization, the control of the fertilized egg is transferred from the egg to the newly formed embryo. A key component of a cells program for controlling the genome consists of chemical labels attached to histone proteins. The histones have a major role in the packaging and regulation of the two meters of DNA found in every cell. The chemical labels attached to these histones make up a code that orchestrates what parts of the DNA to use at a given time. This coding comes "on top of" the DNA, the genetics, and is referred to as "epigenetics". A comparison to a computer can be useful - If considering the DNA, containing our genes, as "hardware" and the program encoded in the epigenetics as the "software" that regulate when, and in what cells certain genes are to be used. Our mapping of the histone code in egg cells from mice resulted in that we discovered a program that is unique to egg cells. This newly discovered program in egg cells and its transfer to the embryo - the next generation, is absolutely required for the formation of a new individual. One may think of this egg cell program as the "software of life", crucial in order for one generation to give rise to the next. Our groundbreaking discoveries was obtained from studies of mouse eggs and embryos, and we will now investigate if the key epigenetic program of egg cells is conserved in eggs from humans and other species. Further, we seek to understand if aberrations in this program is involved in human infertility. We have discovered an enzyme and a mechanism acting in egg cells to protect the egg cell histone modification program. If this mechanism is disrupted through the loss of the enzyme KDM4A, it will result in errors in the egg cell program that is inherited to the embryo and this results in failure in early embryo development. We have further developed our world-leading technology to allow for the study of single oocytes and single embryos. As a result we can gain deeper insight into embryo development.

A long-standing challenge in life science is to understand epigenetic inheritance, its role in maternal-to-zygotic transition (MZT) and epigenetic reprogramming in early embryo development. This knowledge is crucial for understanding the passing of human life from one generation to the next and could be critical for assuring high quality of embryos during assisted reproduction. In order to maximize the success rates of in vitro fertilization (IVF) treatment, patients undergo a controlled ovarian stimulation. As a result, a patient can have multiple fertilized eggs available for embryo transfer and cryopreservation. It is therefore of critical importance to select embryos capable of onward development, implantation, and which may lead to a live birth. Current state of the art approaches typically fails to give a live birth rate of more than 25-30% after transfer of a single embryo to the uterus of a patient. First, we seek to confirm the likely conservation of the key epigenetic program of broad H3K4me3 domains also in human oocytes, building on our recent breakthrough findings in the mouse (Dahl et al., Nature, 2016, 537:548-52). Second, we aim to establish mechanistic insight to the establishment and execution of the newly discovered epigenetic program for early embryo development through studies in the mouse. Third, we aim to elucidate to what extent aberrations in the epigenetic program is responsible for poor IVF outcomes in the clinic. With this proposal we will study the epigenetic mechanisms involved in oocyte developmental competence and gain deeper insight into the basic biology of mammalian embryo development. Understanding this process at the molecular level will provide new tools and open new strategies to diagnose the origin of infertility and improve treatments of this condition. It will also provide new biomarkers useful to predict oocyte and embryo quality during in vitro fertilization, hence holds a realistic potential for innovation.