Study epigenetic inheritance during development and across generations using multiple model organisms

资助父母奖R35 GM127075摘要：DNA复制过程允许基因 要通过单元分裂可靠地复制和传输到其子单元的单元的信息。然而，如果DNA 复制和细胞分裂是以对称的方式进行的，它将导致肿瘤细胞集群而不是 多细胞有机体。例如，一个成年人有超过30万亿个由200多个细胞组成的细胞 单元类型。所有这些具有不同外观和功能的不同细胞都来自同一个细胞--受精卵。 因此，理解任何多细胞生物体的一个中心问题是，细胞如何在忠实的情况下变得不同 保持相同的遗传物质。 解决这个问题对人类健康也有深远的影响。这是因为即使大多数细胞 在我们的体内携带相同的DNA序列，只有这些序列的子集在适当的时间启动表达，在 正确的位置，并与发展和动态平衡期间的准确水平。它是独特的表观遗传信息 包含在每种细胞类型中，定义了其独特的基因表达。在真核细胞中，一种重要的表观遗传学 调节是通过组蛋白的翻译后修饰来实现的。每个~147个碱基的双螺旋DNA围绕着一个 由组蛋白H_2A、H_2B、H_3和H_4蛋白组成的八聚体结构，每种蛋白各有两个拷贝。新成立为法团的 DNA上的组蛋白主要发生在DNA复制过程中，DNA复制除了复制基因组外，还需要 表观基因组的复制。然而，亲本细胞中包含的表观遗传信息如何 在子代细胞中维持或改变的情况在很大程度上仍不清楚。这个问题很难研究。 因为表观基因组是由许多成分组成的，这些成分动态地改变它们的组成。这个问题 对于理解生物学的基本原理和开发新的治疗方法也是极其关键的 人类疾病，因为表观遗传信息的错误调节可能导致发育缺陷或疾病，如 不孕不育、出生缺陷、神经退行性疾病、肌肉营养不良、糖尿病和多种癌症

Abstract of the funded parent award R35 GM127075: The process of DNA replication allows the genetic information of a cell to be copied and transferred reliably to its daughter cells through cell divisions. However, if DNA replication and cell division were carried out in a symmetric manner, it would result in a cluster of tumor cells instead of a multicellular organism. For example, an adult human being has more than 30 trillion cells comprised of more than 200 cell types. All these different cells with distinct appearances and functions originate from a single cell—a fertilized egg. Therefore, a central question to understanding any multicellular organism is how cells become different while faithfully maintaining the same genetic material. Addressing this question also has far-reaching impact on human health. This is because even though most cells in our bodies carry identical DNA sequences, only a subset of these sequences turn on expression at the proper time, in the right place, and with the precise level during development and homeostasis. It is the distinct epigenetic information contained in each cell type that defines its unique gene expression. In eukaryotic cells, an important epigenetic regulation is through post-translational modifications of histones. Every ~147-bp double helix DNA wraps around an octamer structure composed of histone H2A, H2B, H3, and H4 proteins, each in two copies. Incorporation of new histones onto the DNA mainly occurs during DNA replication, which, in addition to copying the genome, requires duplication of the epigenome. However, how the epigenetic information contained in the parental cell can be maintained or changed in the daughter cells remains largely unknown. This question is extremely difficult to study because the epigenome is composed of numerous components that dynamically change their composition. This question is also extremely crucial for understanding the fundamental principles of biology and developing new treatments for human diseases, since mis- regulation of epigenetic information could lead to developmental defects or diseases such as infertility, birth defects, neurodegenerative disease, muscular dystrophy, diabetes, and many forms of cancer