Histone Demethylases and Trophoblast Differentiationt

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Abstract Placental dysfunction leads to pregnancy-associated disorders, including intrauterine growth restriction (IUGR) and preeclampsia, and also serves as a developmental cause for postnatal and adult diseases. Often, the causal alterations in the placentation process, which lead to defective pregnancies, occur early in gestation. Defective development and differentiation of trophoblast progenitors are leading causes for pathological pregnancies. However, we have a poor understanding of molecular mechanisms that regulate trophoblast progenitor self-renewal, differentiation and function in postimplantation embryos. Studies on mutant mouse models and mouse trophoblast stem cells (mouse TSCs) implicated lysine-specific demethylase 1 (LSD1), the first identified histone demethylas, as a critical regulator to prevent premature differentiation of mouse TSCs. However, the importance of LSD1 in the context of differentiated trophoblast cells of a matured placenta is yet to be defined. Also, the importance of LSD1 in human trophoblast development has never been tested. Our preliminary findings establish that LSD1 expression is conserved in trophoblast progenitors across mammalian species, including humans. Thus, in this proposal we will investigate importance of LSD1 in the development of specialized trophoblast cells, namely syncytiotrophoblasts (SynTBs) and invasive trophoblasts, at the maternal- fetal interface. We will also define importance of LSD1 in human trophoblast differentiation and interrogate LSD1 function. Two specific aims are proposed. Aim 1 will study Lsd1 conditional knockout mouse model to test the hypothesis that cell-autonomous function of LSD1 in lineage-specific trophoblast progenitors ensures establishment of differentiated SynTBs and invasive trophoblast cells at the maternal-fetal interface. In Aim 2, using CTB-derived human trophoblast stem cells, we will test the hypothesis that LSD1 establishes a conserved gene expression program in mouse and human trophoblast progenitors and impairment of LSD1-dependent transcriptional program will impair self-renewal and differentiation potential of human trophoblast progenitors. In addition, we will also interrogate significance of LSD1-dependent mechanisms in the context of pathological pregnancies.