Role of SATB in placental development

描述（由申请人提供）：胎盘的生长和发育依赖于被称为滋养细胞干细胞（TS）的干细胞群体的扩增和谱系特异性分化。TS细胞的自我更新和分化是由一个转录调控网络控制的。在细胞分化过程中，染色质重组、重塑和表观遗传变化对基因表达的调控起着基础性的作用。特殊AT-rich sequence binding protein 1 （SATB1）和SATB2是组织特异性基因的染色质组织者和转录调节因子。SATB蛋白结合到DNA的特定基质附着区域，招募染色质重塑酶，并与所需的转录机制相互作用，导致基因激活或基因抑制。它们参与控制T淋巴细胞、成骨细胞、皮质神经元和胚胎干细胞分化的关键基因的转录调控。小鼠胚胎的滋养外胚层细胞表达高水平的SATB蛋白。这些基因在胎盘中的表达随着妊娠的进展而减少，这与TS细胞群的消失是一致的。我们对具有Satb1和/或Satb2零突变的胎盘的初步体内分析表明，Satb1和Satb2对正常胎盘发育至关重要。这两种染色质调节因子在小鼠TS细胞中优先表达，并在滋养细胞分化时下调。初步的体外“功能丧失”研究表明，SATB1和SATB2调节TS细胞的更新和分化。我们认为SATB蛋白通过激活TS细胞自我更新所需的关键基因或抑制导致TS细胞分化的基因，在调节TS细胞自我更新和控制滋养层分化中发挥关键作用。我们计划在小鼠和TS细胞培养模型中研究SATB蛋白在胎盘发育中的作用。这些实验将有助于确定控制TS细胞稳态和胎盘发育的分子机制。揭示TS细胞的基本调控因子将极大地扩展我们对胎盘形态发生和胎盘相关疾病病理生理的理解。

DESCRIPTION (provided by applicant): The growth and development of the placenta is dependent upon expansion and lineage specific differentiation of a population of stem cells referred to as trophoblast stem (TS) cells. Self-renewal of TS cells and differentiation are controlled by a network of transcriptional regulators. Chromatin reorganization, remodeling and epigenetic changes play a fundamental role in the regulation of gene expression during cell differentiation. Special AT-rich sequence binding protein 1 (SATB1) and SATB2 act as chromatin organizers as well as transcriptional regulators of tissue specific genes. SATB proteins bind to specific matrix attachment regions of DNA, recruit chromatin-remodeling enzymes, and interact with the required transcriptional machinery resulting in gene activation or gene repression. They participate in transcriptional regulation of key genes controlling the differentiation of T lymphocytes, osteoblasts, cortical neurons, and embryonic stem cells. The trophectoderm layer of cells in the mouse embryo express high levels of SATB proteins. Expression of these genes diminishes in the placenta with progression of gestation, which coincides with the disappearance of the TS cell population. Our initial in vivo analyses of placentas possessing Satb1 and/or Satb2 null mutations suggest that SATB1 and SATB2 are essential for normal placental development. Both of these chromatin regulators are preferentially expressed in mouse TS cells and downregulated as trophoblast cells differentiate. Preliminary in vitro 'loss-of-function' studies indicate that SATB1 and SATB2 regulate TS cell renewal and differentiation. We propose that SATB proteins play critical roles in regulating self-renewal of TS cells and controlling trophoblast differentiation by activating key genes required for TS cell self-renewal or by repressing genes leading to TS cell differentiation. We plan to examine the role of SATB proteins during placental development in mice and in TS cell culture models. These experiments will lead to the identification of molecular mechanisms controlling TS cell homeostasis and placental development. Revealing the fundamental regulators of TS cells will greatly expand our understanding of placental morphogenesis and the pathophysiology of placenta-associated disorders.