Understanding how the master transcriptional regulator HOXA5 defines cell fate in the developing embryo

了解主转录调节因子 HOXA5 如何定义发育中胚胎的细胞命运

• 批准号: RGPIN-2020-06365
• 负责人: Jeannotte, Lucie
• 金额: $ 2.62万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745057
• 关键词: Understanding; how; master; transcriptional; regulator

Proper control of cell-type specific transcriptional programs is critical for normal development. Mutation of a single transcriptional regulator often produces pleiotropic phenotypes with organ-specific consequences. Therefore, it is fundamental to understand how a single transcription factor confers to cells and tissues their identity by controlling specific transcriptional programs. HOX proteins are evolutionary conserved transcription factors that play critical roles in embryogenesis, organogenesis and tissue homeostasis during postnatal life. Their mutations lead to multiple and various developmental defects and diseases. Despite their broad expression in numerous cell types, HOX proteins perform their regulatory functions in a context-dependent fashion. They bind to similar TNAT motif-rich DNA-binding sites, but confer different regulatory actions in vivo, raising the fundamental question of how specificity of HOX transcriptional outputs is attained. While the developmental role of Hox genes is established, understanding how they act still awaits the identification of target genes. Thus, HOX proteins represent ideal candidates to determine how individual transcription factors govern cell fate. Our long-term objective is to define how HOX transcription factors regulate target gene expression in a highly context-dependent manner during mammalian development. We use HOXA5 as a model, because the loss of Hoxa5 gene function in mice results in a plethora of well-characterized phenotypes and, most importantly, in death at birth due to the combination of respiratory system malformations. These defects include trachea occlusion resulting from cartilage anomalies, lung dysmorphogenesis due to reduced branching, hypoplasia and abnormal cell differentiation, and altered diaphragm innervation and musculature. These phenotypes evoke severe human diseases such as tracheal stenosis, lung hypoplasia and diaphragm eventration. No other single Hox mutants present such an overt respiratory system phenotype revealing the functional predominance of Hoxa5 in this developmental process. Hoxa5 pleiotropic action in the respiratory system suggests cell-specific mechanisms, and makes Hoxa5 an ideal model for studying how individual HOX proteins achieve cell-specificity to orchestrate organ system development. We hypothesize that HOXA5 transcription factor exerts part of its functions through activation of common transcriptional programs but also via the regulation of distinct, context-specific effectors. Our objectives are to define the molecular mechanisms involved in HOXA5 action during the formation of the respiratory system in order to elucidate how HOXA5 attains functional cell-specificity. Our aims are to: 1.Identify and compare the gene networks controlled by the HOXA5 master regulator in the developing trachea, lung and diaphragm 2.Determine the genetic and cellular mechanisms of HOXA5 function in the specific context of trachea formation

适当控制细胞类型的特定转录程序对于正常发育至关重要。单个转录调节剂的突变通常会产生带有器官特异性后果的多效性表型。因此，了解单个转录因子如何通过控制特定的转录程序赋予细胞和组织的身份是至关重要的。 HOX蛋白是进化保守的转录因子，在产后生活中在胚胎发生，器官发生和组织稳态中起关键作用。它们的突变导致多种和各种发育缺陷和疾病。尽管HOX蛋白在众多细胞类型中表达了广泛的表达，但以上下文依赖性的方式执行了调节功能。它们与类似的TNAT基序结合位点结合，但是在体内赋予了不同的调节作用，从而提出了如何达到HOX转录输出特异性的基本问题。尽管建立了HOX基因的发展作用，但了解它们的作用仍在等待靶基因的识别。因此，HOX蛋白代表理想的候选者，以确定单个转录因子如何控制细胞命运。我们的长期目标是在哺乳动物发育过程中定义HOX转录因子如何以高度依赖性方式调节靶基因表达。我们使用HOXA5作为模型，因为小鼠中Hoxa5基因功能的丧失导致了许多特征良好的表型，最重要的是，由于呼吸系统畸形的结合而导致出生时死亡。这些缺陷包括因软骨异常引起的气管阻塞，由于分支减少，发育不全和异常细胞分化以及隔膜神经支配和肌肉的改变而导致的肺部变形。这些表型引起了严重的人类疾病，例如气管狭窄，肺部发育不全和隔膜事件。没有其他单一的HOX突变体提出这种明显的呼吸系统表型，从而揭示了HOXA5在此发育过程中的功能优势。 HOXA5在呼吸系统中的多效性作用提出了细胞特异性机制，并使HOXA5成为研究单个HOX蛋白如何实现细胞特异性的理想模型。我们假设HOXA5转录因子通过激活常见的转录程序，也可以通过调节不同的，上下文特定的效应子来发挥其功能的一部分。我们的目标是定义在呼吸系统形成期间与HOXA5作用相关的分子机制，以阐明HOXA5如何获得功能性细胞特异性。我们的目的是：1。识别和比较由HOXA5主调节器控制的基因网络在发育中的气管，肺和膜片中2.确定HOXA5的遗传和细胞机制在气管形成的特定环境下的遗传和细胞机制功能