At NICHD, our central mission is to ensure that every human is born healthy. Despite much progress in understanding the many ways the mother interacts with the fetus during development, we still know little about the genetic changes that promoted the emergence of placental mammals over 100 million years ago from our egg-laying relatives, nor those mechanisms that continue drive phenotypic differences amongst mammals. One attractive hypothesis is that retroviruses and their endogenization into the genomes of our ancestors played an important role in eutherian evolution, by providing protein coding genes like syncytins (derived from retroviral envgenes that cause cell fusions in placental trophoblasts) and novel gene regulatory nodes that altered expression networks to allow for implantation and the emergence and continued evolution of the placenta. The primary interest of my lab is to explore the impact of these endogenous retroviruses (ERVs), that account for ~10% of our genomic DNA, on embryonic development and on the evolution of new traits in mammals. This has led us to examine the rapidly evolving Kruppel-associated box zinc finger protein (KZFP) family, the single largest family of transcription factors (TFs) in most, if not all mammalian genomes. Our hypothesis is that KZFP gene expansion and diversification has been driven primarily by the constant onslaught of ERVs and other transposable elements (TEs) to the genomes of our ancestors, as a means to transcriptionally repress them. This hypothesis is supported by recent evidence demonstrating the majority of KZFPs bind TEs and that TEs and nearby genes are activated in KZFP knockout mice . In the next several years we will continue to explore the impacts of the TE/KZFP “arms race” on the evolution of mammals. We will also begin a new phase exploring whether KZFPs play broader roles in genome regulation beyond gene silencing, and how these functions impact mammalian development.
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