Histone Demethylases and Trophoblast Differentiationt

摘要 胎盘功能障碍会导致妊娠相关疾病，包括胎儿宫内生长受限 胎儿宫内发育迟缓(IUGR)和先兆子痫，也是导致出生后和成人疾病的发育原因。通常， 胎盘形成过程中导致缺陷妊娠的原因改变发生在早期。 怀孕了。滋养层祖细胞发育和分化缺陷是导致 病理性怀孕。然而，我们对调控的分子机制了解很少。 移植后胚胎中滋养层祖细胞的自我更新、分化和功能。研究：关于 突变的小鼠模型和小鼠滋养层干细胞(小鼠TSCs)涉及赖氨酸特异的脱甲基酶1 第一个被发现的组蛋白去甲基酶(LSD1)，作为防止小鼠过早分化的关键调节因子 TSCS。然而，LSD1在成熟胎盘的分化滋养层细胞中的重要性是 还没有定义。此外，LSD1在人类滋养细胞发育中的重要性从未被测试过。我们的 初步发现LSD1在哺乳动物滋养层祖细胞中的表达是保守的 物种，包括人类。因此，在本提案中，我们将研究LSD1在开发 特化滋养层细胞，即合体滋养层细胞和侵袭性滋养层细胞。 胎儿界面。我们还将确定LSD1在人类滋养细胞分化中的重要性，并询问LSD1 功能。 提出了两个具体目标。Aim 1将研究LSD1条件性基因敲除小鼠模型以测试 假设LSD1在谱系特异性滋养层祖细胞中的细胞自主功能确保 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来源的人滋养层干细胞，我们将检验LSD1的假设 在小鼠和人滋养层祖细胞和损伤中建立保守的基因表达程序 依赖LSD1的转录程序的缺失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LSD1依赖机制在 病理性怀孕的背景。

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.