Histone Demethylases and Trophoblast Differentiationt

摘要 胎盘功能障碍导致妊娠相关疾病，包括宫内生长受限 胎儿生长迟缓（IUGR）和先兆子痫，也是产后和成人疾病的发育原因。很多时候， 胎盘形成过程中的因果变化，导致有缺陷的怀孕，发生在早期， 怀孕滋养层祖细胞的发育和分化缺陷是导致滋养层细胞分化的主要原因。 病理性妊娠然而，我们对调节细胞凋亡的分子机制了解甚少。 滋养层祖细胞自我更新，分化和功能在植入后胚胎。研究 突变小鼠模型和小鼠滋养层干细胞（小鼠TSC）与赖氨酸特异性脱甲基酶1有关 （LSD 1），第一个被鉴定的组蛋白去甲基化酶，作为防止小鼠过早分化的关键调节因子， TSC。然而，LSD 1在成熟胎盘的分化滋养层细胞中的重要性是 还有待确定。此外，LSD 1在人类滋养层发育中的重要性从未被测试过。我们 初步研究结果表明，LSD 1的表达在哺乳动物的滋养层祖细胞中是保守的， 物种，包括人类。因此，在本提案中，我们将研究LSD 1在开发中的重要性， 特化的滋养层细胞，即合体滋养层（SynTB）和侵袭性滋养层，在母体- 胎儿界面我们还将确定LSD 1在人滋养层细胞分化中的重要性， 功能 提出了两个具体目标。目的1研究Lsd 1条件性基因敲除小鼠模型， 假设LSD 1在谱系特异性滋养层祖细胞中细胞自主功能确保 在母胎界面建立分化的SynTB和侵袭性滋养层细胞。 在目标2中，使用CTB衍生的人滋养层干细胞，我们将检验LSD 1 在小鼠和人类滋养层祖细胞中建立了保守的基因表达程序， LSD 1依赖的转录程序的减少将损害人类的自我更新和分化潜能， 滋养层祖细胞此外，我们还将询问LSD 1依赖性机制在 病理性妊娠的背景。

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.