Heterochromatin in the developing vertebrate embryo

项目摘要： DNA分离成开放的常染色质和更浓缩的异染色质是真核生物的基础 基因组组织染色质可及性影响发育中的细胞命运选择及其失调 在疾病中很常见。虽然常染色质和异染色质区室的存在一直是 虽然我们已经认识到这一点超过了世纪，但我们仍然对驱动最初的、快速的 在胚胎发生过程中，基因组分成这些不同的结构域。虽然我们和其他人 已经表明，异染色质的大规模从头建立是紧密相连的发病， 合子基因在动物中的表达，加速或延迟转录的后果 在脊椎动物发育早期窗口期异染色质的建立是未知的。我 实验室专注于组蛋白H3赖氨酸9三甲基（H3K9me3）标记的异染色质，它形成了 脊椎动物异染色质的主要块。沉默需要H3K9me3标记的异染色质 转座子，抑制不适当的重组，适当的染色体分离和适当的 转录发育重要基因。在这里，我们提出了一个创新的计划， 基因组和分子生物学方法，旨在揭示控制大细胞的机制， H3K9me3标记的异染色质在早期脊椎动物胚胎发生过程中的规模从头建立， 以确定胚胎中异染色质建立时间改变的后果。我们选择 斑马鱼作为模型，因为在斑马鱼的异染色质调节和 哺乳动物，而且因为斑马鱼胚胎的外部受精促进了 在非常早期的发展中。在我们的研究过程中，我们将阐明几个功能 新鉴定的异染色质建立的调节因子， 指导从头异染色质的形成，并阐明5-甲基胞嘧啶和 H3K9me3在早期胚胎发生中的作用。我们还将确定受以下因素影响的早期发展计划： 改变胚胎中异染色质建立的时间轴。这项研究意义重大，因为它 解决了我们对异染色质形成的理解中的关键和长期存在的知识空白， 在早期脊椎动物胚胎发育中起作用。了解异染色质是如何首先建立在 发育，以及它在调节早期转录中的功能，对于我们了解它是如何 异染色质失调导致疾病，以及我们如何干预以重置异常染色质 使用靶向治疗的国家。

Project Summary: Segregation of DNA into open euchromatin and more condensed heterochromatin is fundamental to eukaryotic genome organization. Chromatin accessibility influences cell-fate choice in development and its dysregulation is common in disease. While the presence of euchromatic and heterochromatic compartments has been appreciated for over a century, we still know almost nothing about the mechanisms that drive the initial, rapid fractionation of genomes into these distinct domains during embryogenesis. Moreover, although we and others have shown that the large-scale de novo establishment of heterochromatin is tightly linked to the onset of zygotic gene expression in animals, the transcriptional consequences of accelerating or delaying heterochromatin establishment during this early window of vertebrate development are not known. My laboratory focuses on Histone H3 lysine 9 trimethyl (H3K9me3) marked heterochromatin, which forms the major blocks of heterochromatin in vertebrates. H3K9me3 marked heterochromatin is required for the silencing of transposons, suppression of inappropriate recombination, proper chromosome segregation and appropriate transcription of developmentally important genes. Here, we propose an innovative program combining genetic, genomic and molecular biology approaches, which seeks to uncover the mechanisms that control the large- scale de novo establishment of H3K9me3 marked heterochromatin during early vertebrate embryogenesis and to define the consequences of shifting the timing of heterochromatin establishment in the embryo. We choose zebrafish as a model because there are clear parallels between heterochromatin regulation in zebrafish and in mammals, and because external fertilization of the zebrafish embryo facilitates the molecular interrogation of chromatin in very early development. Over the course of our studies, we will elucidate the functions of several newly identified regulators of heterochromatin establishment, test requirements for zygotic transcripts in directing de novo heterochromatin formation and clarify the relationship between 5-methylcytosine and H3K9me3 in early embryogenesis. We will also identify early developmental programs that are impacted by altering the timeline of heterochromatin establishment in the embryo. This research is significant, as it addresses critical and long-standing knowledge gaps in our understanding of heterochromatin formation and function during early vertebrate embryogenesis. Understanding how heterochromatin is first established during development, and its functions in regulating early transcription is necessary for us to understand how heterochromatin misregulation contributes to disease, and how we might intervene to reset aberrant chromatin states using targeted therapies.