Grant: Project Grant

While all cells of an organism have essentially the same genetic sequence, their genome, the addition of chemical modifications directly on DNA, such as methylation, can influence what genes are expressed or silenced in different cell types. During germline development, the process by which mature eggs and sperm are produced, DNA marks are first erased in the developing embryo and then re-established according to the sex of the embryo. During the formation of mature eggs, the establishment of DNA methylation patterns occurs after birth and is guided by gene expression: the body of expressed genes acquires DNA methylation. Some of these maternal marks are responsible for the expression of certain genes, called imprinted genes, only from the un-methylated paternal copy in the embryo. Imprinted genes play important roles in the regulation of embryonic growth and are linked to several human imprinting disorders. We recently showed that some of the egg's gene expression and DNA methylation are controlled by repetitive retroviral-like sequences in human and mouse. We hypothesize that these repetitive sequences, which are highly divergent between species, have contributed to the evolution of new imprinted genes. In this project, we will first study the functions of human genes expressed only from their paternal copy in the placenta, a key organ controlling embryonic growth. We will also study the molecular mechanism whereby retroviral-like sequences are implicated in the acquisition of DNA marks in the egg, using new mouse models. These studies, aimed at confirming our hypothesis, will yield new fundamental knowledge of processes required for normal development and associated with a number of inborn diseases in humans. They will directly test a new evolutionary function for retroviral-like sequences and provide critical functional data on human placental genes that might have been selected for imprinted expression because of their importance in regulating embryonic growth.