Role of SATB in placental development

SATB 在胎盘发育中的作用

• 批准号: 8283288
• 负责人: Mohammad A.K. Rumi
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283288
• 关键词: AT Rich Sequence; Binding Proteins; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cell Proliferation Regulation; Cells; Cerebral cortex; Chromatin; Chromatin Remodeling Factor; DNA; Development; Disease; Embryo; Enzymes; Epigenetic Process; Exhibits; Fetal Development; Functional disorder; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genome; Goals; Growth; Growth and Development function; Health; Homeostasis; In Vitro; Lead; Matrix Attachment Regions; Modeling; Molecular; Morphogenesis; Mus; Neurons; Osteoblasts; Phenotype; Placenta; Placentation; Play; Pregnancy; Pregnancy Complications; Property; Protein Binding; Proteins; Recruitment Activity; Regulation; Role; Stem cells; T-Lymphocyte; Thymus Gland; Tissues; Transcriptional Regulation; chromatin remodeling; craniofacial; design; embryonic stem cell; fetal; gain of function mutation; gene repression; in vivo; insight; loss of function; loss of function mutation; mutant; novel; null mutation; preimplantation; research study; self-renewal; stem cell differentiation; stem cell division; stem cell population; success; trophoblast

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. PUBLIC HEALTH RELEVANCE: Proper development of the placenta is essential for fetal development and pregnancy success. Growth and development of the placenta are dependent on proliferation and lineage-specific differentiation of trophoblast stem cells. Understanding the molecular mechanisms that regulate trophoblast stem cells during development is critical for gaining insights into placenta associated disorders that can negatively impact maternal and fetal health.

描述（由申请人提供）：胎盘的生长和发育取决于被称为滋养层干（TS）细胞的干细胞群的扩增和谱系特异性分化。 TS 细胞的自我更新和分化由转录调节因子网络控制。染色质重组、重塑和表观遗传变化在细胞分化过程中基因表达的调节中发挥着重要作用。特殊的富含 AT 的序列结合蛋白 1 (SATB1) 和 SATB2 充当染色质组织者以及组织特异性基因的转录调节剂。 SATB 蛋白与 DNA 的特定基质附着区域结合，招募染色质重塑酶，并与所需的转录机制相互作用，从而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。随着妊娠的进展，这些基因在胎盘中的表达逐渐减少，这与 TS 细胞群的消失相一致。我们对具有 Satb1 和/或 Satb2 无效突变的胎盘进行的初步体内分析表明，SATB1 和 SATB2 对于正常胎盘发育至关重要。这两种染色质调节因子均优先在小鼠 TS 细胞中表达，并随着滋养层细胞的分化而下调。初步体外“功能丧失”研究表明 SATB1 和 SATB2 调节 TS 细胞更新和分化。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通过抑制导致 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。我们计划研究 SATB 蛋白在小鼠胎盘发育和 TS 细胞培养模型中的作用。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 细胞的基本调节因子将极大地扩展我们对胎盘形态发生和胎盘相关疾病的病理生理学的理解。 公共卫生相关性：胎盘的正常发育对于胎儿发育和妊娠成功至关重要。胎盘的生长和发育依赖于滋养层干细胞的增殖和谱系特异性分化。了解发育过程中调节滋养层干细胞的分子机制对于深入了解可能对母婴健康产生负面影响的胎盘相关疾病至关重要。